bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒04‒02
58 papers selected by
Peio Azcoaga
Biodonostia HRI
  1. Crosstalk between triple negative breast cancer and microenvironment.
  2. The Role of PRMT5 in Immuno-Oncology.
  3. Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth.
  4. The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer.
  5. Bioinformatic miRNA-mRNAs Analysis Revels to miR-934 as a Potential Regulator of the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer.
  6. Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells.
  7. Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer.
  8. The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.
  9. Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.
  10. Tumor Cell-Autonomous SHP2 Contributes to Immune Suppression in Metastatic Breast Cancer.
  11. Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers.
  12. Mechanisms of Organ-Specific Metastasis of Breast Cancer.
  13. RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis.
  14. The role of macrophages in the tumor microenvironment and tumor metabolism.
  15. PD-1 monoclonal antibodies enhance the cryoablation-induced antitumor immune response: a breast cancer murine model research.
  16. Knowing the myeloid-derived suppressor cells: Another enemy of sarcomas patients.
  17. Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.
  18. Metformin plays an antitumor role by downregulating inhibitory cells and immune checkpoint molecules while activating protective immune responses in breast cancer.
  19. Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts.
  20. Neutrophil extracellular traps in tumor progression and immunotherapy.
  21. Methionine enkephalin suppresses lung cancer metastasis by regulating the polarization of tumor-associated macrophages and the distribution of myeloid-derived suppressor cells in the tumor microenvironment and inhibiting epithelial-mesenchymal transition.
  22. Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low.
  23. Cancer-cell-intrinsic mechanisms regulate MDSCs through cytokine networks.
  24. Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles.
  25. Survivin (BIRC5) Peptide Vaccine in the 4T1 Murine Mammary Tumor Model: A Potential Neoadjuvant T Cell Immunotherapy for Triple Negative Breast Cancer: A Preliminary Study.
  26. Monocyte and Macrophage in Neuroblastoma: Blocking Their Pro-Tumoral Functions and Strengthening Their Crosstalk with Natural Killer Cells.
  27. Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases.
  28. Fatty acid metabolism and radiation-induced anti-tumor immunity.
  29. The role of Th-17 cells and IL-17 in the metastatic spread of breast cancer: As a means of prognosis and therapeutic target.
  30. Tumor-Infiltrating Immune Cell Landscapes in the Lymph Node Metastasis of Papillary Thyroid Cancer.
  31. Overexpressed Malat1 Drives Metastasis through Inflammatory Reprogramming of Lung Adenocarcinoma Microenvironment.
  32. Role and Potential of Different T Helper Cell Subsets in Adoptive Cell Therapy.
  33. Differential Transcriptome Responses in Human THP-1 Macrophages Following Exposure to T98G and LN-18 Human Glioblastoma Secretions: A Simplified Bioinformatics Approach to Understanding Patient-Glioma-Specific Effects on Tumor-Associated Macrophages.
  34. Inflammation, Infiltration, and Evasion-Tumor Promotion in the Aging Breast.
  35. Tamoxifen Modulates the Immune Landscape of the Tumour Microenvironment: The Paired Siglec-5/14 Checkpoint in Anti-Tumour Immunity in an In Vitro Model of Breast Cancer.
  36. Nucleotide metabolism: a pan-cancer metabolic dependency.
  37. The effects of MYC on tumor immunity and immunotherapy.
  38. The Role of Reprogrammed Glucose Metabolism in Cancer.
  39. TGF-β signaling pathway: Therapeutic targeting and potential for anti-cancer immunity.
  40. Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas.
  41. GATA-3 expression in breast cancer is related to intratumoral M2 macrophage infiltration and tumor differentiation.
  42. Cytotoxic Lymphocyte-Related Gene Signature in Triple-Negative Breast Cancer.
  43. Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
  44. IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines.
  45. Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies.
  46. TREM2: A new player in the tumor microenvironment.
  47. Redox dysregulation in the tumor microenvironment contributes to cancer metastasis.
  48. Role of Heterogeneous Nuclear Ribonucleoproteins in the Cancer-Immune Landscape.
  49. Exploring the Role of Hypoxia-Inducible Carbonic Anhydrase IX (CAIX) in Circulating Tumor Cells (CTCs) of Breast Cancer.
  50. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.
  51. Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer.
  52. CD47-blocking Antibody ZL-1201 Promotes Tumor-associated Macrophage Phagocytic Activity and Enhances the Efficacy of the Therapeutic Antibodies and Chemotherapy.
  53. IL-12 and IL-27 Promote CD39 Expression on CD8+ T Cells and Differentially Regulate the CD39+CD8+ T Cell Phenotype.
  54. Pexidartinib synergize PD-1 antibody through inhibiting treg infiltration by reducing TAM-derived CCL22 in lung adenocarcinoma.
  55. A progressive T cell exhaustion program mapped across tissues in patients with lung cancer on immune checkpoint blockade.
  56. Terminally exhausted CD8+ T cells resistant to PD-1 blockade promote generation and maintenance of aggressive cancer stem cells.
  57. Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
  58. Multiplexed repression of immunosuppressive genes as combinatorial cancer immunotherapy.
  1. Oncotarget. 2023 Mar 31. 14 284-293
    Crosstalk between triple negative breast cancer and microenvironment.
    Karly Smrekar, Artem Belyakov, Kideok Jin.
      Although many advances have been made in the treatment of breast cancer, for the triple negative breast cancer (TNBC) these therapies have not significantly increased overall survival. Tumor microenvironment (TME) plays an essential role to develop and control TNBC progression. Many preclinical and clinical studies are ongoing to treat patients with TNBC disease, but the effective therapies are currently not available. Here, we have reviewed recent progress in understanding of TNBC and advance in defining mechanisms of TNBC therapies and potential therapeutic strategies to overcome TNBC.
    Keywords:  current therapy; triple negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.18632/oncotarget.28397
  2. Genes (Basel). 2023 Mar 09. pii: 678. [Epub ahead of print]14(3):
    The Role of PRMT5 in Immuno-Oncology.
    Yoshinori Abe, Takumi Sano, Nobuyuki Tanaka.
      Immune checkpoint inhibitor (ICI) therapy has caused a paradigm shift in cancer therapeutic strategy. However, this therapy only benefits a subset of patients. The difference in responses to ICIs is believed to be dependent on cancer type and its tumor microenvironment (TME). The TME is favorable for cancer progression and metastasis and can also help cancer cells to evade immune attacks. To improve the response to ICIs, it is crucial to understand the mechanism of how the TME is maintained. Protein arginine methyltransferase 5 (PRMT5) di-methylates arginine residues in its substrates and has essential roles in the epigenetic regulation of gene expression, signal transduction, and the fidelity of mRNA splicing. Through these functions, PRMT5 can support cancer cell immune evasion. PRMT5 is necessary for regulatory T cell (Treg) functions and promotes cancer stemness and the epithelial-mesenchymal transition. Specific factors in the TME can help recruit Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells into tumors. In addition, PRMT5 suppresses antigen presentation and the production of interferon and chemokines, which are necessary to recruit T cells into tumors. Overall, PRMT5 supports an immunosuppressive TME. Therefore, PRMT5 inhibition would help recover the immune cycle and enable the immune system-mediated elimination of cancer cells.
    Keywords:  PRMT5; immune checkpoint; immune evasion; immuno-oncology; tumor microenvironment
    DOI:  https://doi.org/10.3390/genes14030678
  3. Int J Mol Sci. 2023 Mar 09. pii: 5278. [Epub ahead of print]24(6):
    Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth.
    Emilija Zapletal, Tea Vasiljevic, Pierre Busson, Tanja Matijevic Glavan.
      Damage-associated molecular patterns (DAMPs) are endogenous molecules released from the necrotic cells dying after exposure to various stressors. After binding to their receptors, they can stimulate various signaling pathways in target cells. DAMPs are especially abundant in the microenvironment of malignant tumors and are suspected to influence the behavior of malignant and stromal cells in multiple ways often resulting in promotion of cell proliferation, migration, invasion, and metastasis, as well as increased immune evasion. This review will start with a reminder of the main features of cell necrosis, which will be compared to other forms of cell death. Then we will summarize the various methods used to assess tumor necrosis in clinical practice including medical imaging, histopathological examination, and/or biological assays. We will also consider the importance of necrosis as a prognostic factor. Then the focus will be on the DAMPs and their role in the tumor microenvironment (TME). We will address not only their interactions with the malignant cells, frequently leading to cancer progression, but also with the immune cells and their contribution to immunosuppression. Finally, we will emphasize the role of DAMPs released by necrotic cells in the activation of Toll-like receptors (TLRs) and the possible contributions of TLRs to tumor development. This last point is very important for the future of cancer therapeutics since there are attempts to use TLR artificial ligands for cancer therapeutics.
    Keywords:  HMGB1; RAGE; Toll-like receptors; cancer; damage-associated molecular patterns (DAMPs); necrosis; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ijms24065278
  4. Cancer Res Commun. 2023 Jan;3(1): 160-174
    The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer.
    Priyanka S Rana, Wei Wang, Vesna Markovic, Justin Szpendyk, Ernest Ricky Chan, Khalid Sossey-Alaoui.
      Breast cancer is the most frequently diagnosed malignancy in women and the major cause of death because of its invasion, metastasis, and resistance to therapies capabilities. The most aggressive subtype of breast cancer is triple-negative breast cancer (TNBC) due to invasive and metastatic properties along with early age of diagnosis and poor prognosis. TNBC tumors do not express estrogen, progesterone, and HER2 receptors, which limits their treatment with targeted therapies. Cancer invasiveness and metastasis are known to be promoted by increased cell motility and upregulation of the WAVE proteins. While the contribution of WAVE2 to cancer progression is well documented, the WAVE2-mediated regulation of TNBC oncogenic properties is still under investigated, as does the molecular mechanisms by which WAVE2 regulates such oncogenic pathways. In this study, we show that WAVE2 plays a significant role in TNBC development, progression, and metastasis, through the regulation of miR-29 expression, which in turn targets Integrin-β1 (ITGB1) and its downstream oncogenic activities. Conversely, we found WAVE2 expression to be regulated by miR-29 in a negative regulatory feedback loop. Reexpression of exogenous WAVE2 in the WAVE2-deficient TNBC cells resulted in reactivation of ITGB1 expression and activity, further confirming the specificity of WAVE2 in regulating Integrin-β1. Together, our data identify a novel WAVE2/miR-29/ITGB1 signaling axis, which is essential for the regulation of the invasion-metastasis cascade in TNBC. Our findings offer new therapeutic strategies for the treatment of TNBC by targeting WAVE2 and/or its downstream effectors.Significance: Identification of a novel WAVE2/miR-29/ITGB1 signaling axis may provide new insights on how WAVE2 regulates the invasion-metastasis cascade of TNBC tumors through the modulation of ITGB1 and miR-29.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0249
  5. Cells. 2023 Mar 08. pii: 834. [Epub ahead of print]12(6):
    Bioinformatic miRNA-mRNAs Analysis Revels to miR-934 as a Potential Regulator of the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer.
    Jorge Alberto Contreras-Rodríguez, Jonathan Puente-Rivera, Diana Margarita Córdova-Esparza, Stephanie I Nuñez-Olvera, Macrina Beatriz Silva-Cázares.
      Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer and has the worst prognosis. In patients with TNBC tumors, the tumor cells have been reported to have mesenchymal features, which help them migrate and invade. Various studies on cancer have revealed the importance of microRNAs (miRNAs) in different biological processes of the cell in that aberrations, in their expression, lead to alterations and deregulations in said processes, giving rise to tumor progression and aggression. In the present work, we determined the miRNAs that are deregulated in the epithelial-mesenchymal transition process in breast cancer. We discovered that 25 miRNAs that regulate mesenchymal genes are overexpressed in patients with TNBC. We found that miRNA targets modulate different processes and pathways, such as apoptosis, FoxO signaling pathways, and Hippo. We also found that the expression level of miR-934 is specific to the molecular subtype of the triple-negative breast cancer and modulates a set of related epithelial-mesenchymal genes. We determined that miR-934 inhibition in TNBC cell lines inhibits the migratory abilities of tumor cells.
    Keywords:  mesenchymal–epithelium transition; miR-934–PTEN–EGR2 axis; miRNAs; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cells12060834
  6. Int J Mol Sci. 2023 Mar 08. pii: 5208. [Epub ahead of print]24(6):
    Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells.
    María Luisa Sánchez-León, Carlos Jiménez-Cortegana, Silvia Silva Romeiro, Carmen Garnacho, Luis de la Cruz-Merino, Daniel J García-Domínguez, Lourdes Hontecillas-Prieto, Víctor Sánchez-Margalet.
      Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.
    Keywords:  breast cancer; immunotherapy; myeloid-derived suppressor cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms24065208
  7. Int J Mol Sci. 2023 Mar 15. pii: 5600. [Epub ahead of print]24(6):
    Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer.
    Sonia Ben Hamouda, Khadija Essafi-Benkhadir.
      The study of the tumor microenvironment (TME) has become an important part of colorectal cancer (CRC) research. Indeed, it is now accepted that the invasive character of a primary CRC is determined not only by the genotype of the tumor cells, but also by their interactions with the extracellular environment, which thereby orchestrates the development of the tumor. In fact, the TME cells are a double-edged sword as they play both pro- and anti-tumor roles. The interaction of the tumor-infiltrating cells (TIC) with the cancer cells induces the polarization of the TIC, exhibiting an antagonist phenotype. This polarization is controlled by a plethora of interconnected pro- and anti-oncogenic signaling pathways. The complexity of this interaction and the dual function of these different actors contribute to the failure of CRC control. Thus, a better understanding of such mechanisms is of great interest and provides new opportunities for the development of personalized and efficient therapies for CRC. In this review, we summarize the signaling pathways linked to CRC and their implication in the development or inhibition of the tumor initiation and progression. In the second part, we enlist the major components of the TME and discuss the complexity of their cells functions.
    Keywords:  colorectal cancer; dual function; effectors; signaling pathways; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms24065600
  8. Biomed Pharmacother. 2023 May;pii: S0753-3322(23)00292-5. [Epub ahead of print]161 114504
    The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.
    Lunxu Li, Yu Tian.
      Macrophages are potent immune effector cells in innate immunity and exert dual-effects in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) make up a significant portion of TME immune cells. Similar to M1/M2 macrophages, TAMs are also highly plastic, and their functions are regulated by cytokines, chemokines and other factors in the TME. The metabolic changes in TAMs are significantly associated with polarization towards a protumour or antitumour phenotype. The metabolites generated via TAM metabolic reprogramming in turn promote tumor progression and immune tolerance. In this review, we explore the metabolic reprogramming of TAMs in terms of energy, amino acid and fatty acid metabolism and the potential roles of these changes in immune suppression.
    Keywords:  Immunosuppression; Metabolism; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.biopha.2023.114504
  9. Biomed Pharmacother. 2023 Mar 27. pii: S0753-3322(23)00389-X. [Epub ahead of print]162 114601
    Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.
    Xihe Zhao, Kai Li, Mengyu Chen, Lei Liu.
      Oncogenesis and the development of tumors affect metabolism throughout the body. Metabolic reprogramming (also known as metabolic remodeling) is a feature of malignant tumors that is driven by oncogenic changes in the cancer cells themselves as well as by cytokines in the tumor microenvironment. These include endothelial cells, matrix fibroblasts, immune cells, and malignant tumor cells. The heterogeneity of mutant clones is affected by the actions of other cells in the tumor and by metabolites and cytokines in the microenvironment. Metabolism can also influence immune cell phenotype and function. Metabolic reprogramming of cancer cells is the result of a convergence of both internal and external signals. The basal metabolic state is maintained by internal signaling, while external signaling fine-tunes the metabolic process based on metabolite availability and cellular needs. This paper reviews the metabolic characteristics of gastric cancer, focusing on the intrinsic and extrinsic mechanisms that drive cancer metabolism in the tumor microenvironment, and interactions between tumor cell metabolic changes and microenvironment metabolic changes. This information will be helpful for the individualized metabolic treatment of gastric cancers.
    Keywords:  Codependencies; Gastric cancer; Immunal reprogramming; Metabolism; Microenviroment
    DOI:  https://doi.org/10.1016/j.biopha.2023.114601
  10. Cancer Res Commun. 2022 Oct;2(10): 1104-1118
    Tumor Cell-Autonomous SHP2 Contributes to Immune Suppression in Metastatic Breast Cancer.
    Hao Chen, Gregory M Cresswell, Sarah Libring, Mitchell G Ayers, Jinmin Miao, Zhong-Yin Zhang, Luis Solorio, Timothy L Ratliff, Michael K Wendt.
      SH2 containing protein tyrosine phosphatase-2 (SHP2) is recognized as a druggable oncogenic phosphatase that is expressed in both tumor cells and immune cells. How tumor cell-autonomous SHP2 contributes to an immunosuppressive tumor microenvironment (TME) and therapeutic failure of immune checkpoint blockades in metastatic breast cancer (MBC) is not fully understood. Herein, we utilized systemic SHP2 inhibition and inducible genetic depletion of SHP2 to investigate immune reprogramming during SHP2 targeting. Pharmacologic inhibition of SHP2 sensitized MBC cells growing in the lung to α-programmed death ligand 1 (α-PD-L1) antibody treatment via relieving T-cell exhaustion induced by checkpoint blockade. Tumor cell-specific depletion of SHP2 similarly reduced pulmonary metastasis and also relieved exhaustion markers on CD8+ and CD4+ cells. Both systemic SHP2 inhibition and tumor cell-autonomous SHP2 depletion reduced tumor-infiltrated CD4+ T cells and M2-polarized tumor-associated macrophages. Analysis of TCGA datasets revealed that phosphorylation of SHP2 is important for immune-cell infiltration, T-cell activation and antigen presentation. To investigate this mechanistically, we conducted in vitro T-cell killing assays, which demonstrated that pretreatment of tumor cells with FGF2 and PDGF reduced the cytotoxicity of CD8+ T cells in a SHP2-dependent manner. Both growth factor receptor signaling and three-dimensional culture conditions transcriptionally induced PD-L1 via SHP2. Finally, SHP2 inhibition reduced MAPK signaling and enhanced STAT1 signaling, preventing growth factor-mediated suppression of MHC class I. Overall, our findings support the conclusion that tumor cell-autonomous SHP2 is a key signaling node utilized by MBC cells to engage immune-suppressive mechanisms in response to diverse signaling inputs from TME.Significance: Findings present inhibition of SHP2 as a therapeutic option to limit breast cancer metastasis by promoting antitumor immunity.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0117
  11. Cancers (Basel). 2023 Mar 22. pii: 1899. [Epub ahead of print]15(6):
    Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers.
    Kellen Wright, Thuc Ly, Matthew Kriet, Andras Czirok, Sufi Mary Thomas.
      Cancer cells rely on the tumor microenvironment (TME), a composite of non-malignant cells, and extracellular matrix (ECM), for survival, growth, and metastasis. The ECM contributes to the biomechanical properties of the surrounding tissue, in addition to providing signals for tissue development. Cancer-associated fibroblasts (CAFs) are stromal cells in the TME that are integral to cancer progression. Subtypes of CAFs across a variety of cancers have been revealed, and each play a different role in cancer progression or suppression. CAFs secrete signaling molecules and remodel the surrounding ECM by depositing its constituents as well as degrading enzymes. In cancer, a remodeled ECM can lead to tumor-promoting effects. Not only does the remodeled ECM promote growth and allow for easier metastasis, but it can also modulate the immune system. A better understanding of how CAFs remodel the ECM will likely yield novel therapeutic targets. In this review, we summarize the key factors secreted by CAFs that facilitate tumor progression, ECM remodeling, and immune suppression.
    Keywords:  cancer-associated fibroblasts; extracellular matrix; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15061899
  12. Cold Spring Harb Perspect Med. 2023 Mar 27. pii: a041326. [Epub ahead of print]
    Mechanisms of Organ-Specific Metastasis of Breast Cancer.
    Emma Nolan, Yibin Kang, Ilaria Malanchi.
      Cancer metastasis, or the development of secondary tumors in distant tissues, accounts for the vast majority of fatalities in patients with breast cancer. Breast cancer cells show a striking proclivity to metastasize to distinct organs, specifically the lung, liver, bone, and brain, where they face unique environmental pressures and a wide variety of tissue-resident cells that together create a strong barrier for tumor survival and growth. As a consequence, successful metastatic colonization is critically dependent on reciprocal cross talk between cancer cells and host cells within the target organ, a relationship that shapes the formation of a tumor-supportive microenvironment. Here, we discuss the mechanisms governing organ-specific metastasis in breast cancer, focusing on the intricate interactions between metastatic cells and specific niche cells within a secondary organ, and the remarkable adaptations of both compartments that cooperatively support cancer growth. More broadly, we aim to provide a framework for the microenvironmental prerequisites within each distinct metastatic site for successful breast cancer metastatic seeding and outgrowth.
    DOI:  https://doi.org/10.1101/cshperspect.a041326
  13. Oncogene. 2023 Mar 30.
    RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis.
    Jie Zhang, Hailin Tu, Zheyu Zheng, Xueqiang Zhao, Xin Lin.
      It is well established that interferon (IFN) and tumor necrosis factor (TNF) could synergistically promote antitumor toxicity and avoid resistance of antigen-negative tumors during cancer immunotherapy. The linear ubiquitin chain assembly complex (LUBAC) has been widely known to regulate receptor-interacting protein kinase-1(RIPK1) kinase activity and TNF-mediated cell death during inflammation and embryogenesis. However, whether LUBAC and RIPK1 kinase activity in tumor microenvironment could regulate antitumor immunity are still not very clear. Here, we demonstrated a cancer cell-intrinsic role of LUBAC complex in tumor microenvironment to promote tumorigenesis. Lacking LUBAC component RNF31 in B16 melanoma cells but not immune cells including macrophages or dendritic cells greatly impaired tumor growth by increasing intratumoral CD8+ T cells infiltration. Mechanistically, we found that tumor cells without RNF31 shown severe apoptosis-mediated cell death caused by TNFα/IFNγ in the tumor microenvironment. Most importantly, we found that RNF31 could limit RIPK1 kinase activity and further prevent tumor cell death in a transcription-independent manner, suggesting a crucial role of RIPK1 kinase activity in tumorigenesis. Together, our results demonstrate an essential role of RNF31 and RIPK1 kinase activity in tumorigenesis and imply that RNF31 inhibition could be harnessed to enhance antitumor toxicity during tumor immunotherapy.
    DOI:  https://doi.org/10.1038/s41388-023-02669-8
  14. Semin Immunopathol. 2023 Mar 31.
    The role of macrophages in the tumor microenvironment and tumor metabolism.
    Pritam Sadhukhan, Tanguy Y Seiwert.
      The complexity and plasticity of the tumor microenvironment (TME) make it difficult to fully understand the intratumoral regulation of different cell types and their activities. Macrophages play a crucial role in the signaling dynamics of the TME. Among the different subtypes of macrophages, tumor-associated macrophages (TAMs) are often associated with poor prognosis, although some subtypes of TAMs can at the same time improve treatment responsiveness and lead to favorable clinical outcomes. TAMs are key regulators of cancer cell proliferation, metastasis, angiogenesis, extracellular matrix remodeling, tumor metabolism, and importantly immunosuppression in the TME by modulating various chemokines, cytokines, and growth factors. TAMs have been identified as a key contributor to resistance to chemotherapy and cancer immunotherapy. In this review article, we aim to discuss the mechanisms by which TAMs regulate innate and adaptive immune signaling in the TME and summarize recent preclinical research on the development of therapeutics targeting TAMs and tumor metabolism.
    Keywords:  Immune evasion; Metabolism; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00281-023-00988-2
  15. Int J Hyperthermia. 2023 ;40(1): 2164625
    PD-1 monoclonal antibodies enhance the cryoablation-induced antitumor immune response: a breast cancer murine model research.
    Ze-Peng Yu, Xing-Wei Sun, Ya-Ping He, Jun Gu, Yong Jin.
      BACKGROUND: It has been demonstrated that cryoablation (Cryo) causes specific T-cell immune responses in the body; however, it is not sufficient to prevent tumor recurrence and metastasis. In this report, we evaluated changes in the tumor immune microenvironment (TIME) in distant tumor tissues after Cryo and investigated the immunosuppressive mechanisms that limit the efficacy of Cryo.METHODS: Bilateral mammary tumor models were established in mice, and we first observed the dynamic changes in immune cells and cytokines at different time points after Cryo. Then, we confirmed that the upregulation of PD-1 and PD-L1 signaling in the contralateral tumor tissue was closely related to the immunosuppressive state in the TIME at the later stage after Cryo. Finally, we also evaluated the synergistic antitumor effects of Cryo combined with PD-1 monoclonal antibody (mAb) in the treatment of breast cancer (BC) mouse.
    RESULTS: We found that Cryo can stimulate the body's immune response, but it also induces immunosuppression. The elevated PD-1/PD-L1 expression in distant tumor tissues at the later stage after Cryo was closely related to the immunosuppressive state in the TIME but also created the conditions for Cryo combined with PD-1 mAb for BC mouse treatment. Cryo + PD-1 mAb could improve the immunosuppressive state of tumors and enhance the Cryo-induced immune response, thus exerting a synergistic antitumor effect.
    CONCLUSIONS: The PD-1/PD-L1 axis plays an important role in suppressing Cryo-induced antitumor immune responses. This study provides a theoretical basis for Cryo combined with PD-1 mAb therapy in clinical BC patients.
    Keywords:  PD-1 monoclonal antibodies; breast cancer; cryoablation; immune response; immunosuppression
    DOI:  https://doi.org/10.1080/02656736.2022.2164625
  16. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(22)00141-1. [Epub ahead of print]375 93-116
    Knowing the myeloid-derived suppressor cells: Another enemy of sarcomas patients.
    Daniel J García-Domínguez, Víctor Sánchez-Margalet, Luis de la Cruz-Merino, Lourdes Hontecillas-Prieto.
      Sarcomas are heterogeneous and aggressive malignant tumors with variable responses to current standard treatments being usually incurable for those patients with metastatic and unresectable diseases. The lack of curative strategies has led to develop new therapies in the treatment of sarcomas where the role of immune system is an evolving field. Most sarcomas often exhibit an immunosuppressive microenvironment, which reduces their capacity to trigger an immune response. Therefore, sarcomas are broadly considered as an "immune cold" tumor, although some studies have described a great immune heterogeneity across sarcoma subtypes. Sarcoma cells, like other tumors, evade their immune destruction through a variety of mechanisms, including expansion and recruitment of myeloid derived suppressor cells (MDSCs). MDSCs are immature myeloid cells that have been correlated with a reduction of the therapeutic efficacy, including immunotherapy, tumor progression and worst prognosis. Consequently, different strategies have been developed in recent years to target MDSCs in cancer treatments. This chapter discusses the role of MDSCs in sarcomas and their current potential as a therapeutic target in these malignancies.
    Keywords:  Myeloid derived suppressor cells; Sarcomas; Therapeutic target
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.11.003
  17. bioRxiv. 2023 Mar 11. pii: 2023.03.09.532000. [Epub ahead of print]
    Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer.
    Patrick E Gelbach, Stacey D Finley.
      1Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment, which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the tumor microenvironment. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.
    DOI:  https://doi.org/10.1101/2023.03.09.532000
  18. Int Immunopharmacol. 2023 Mar 28. pii: S1567-5769(23)00359-4. [Epub ahead of print]118 110038
    Metformin plays an antitumor role by downregulating inhibitory cells and immune checkpoint molecules while activating protective immune responses in breast cancer.
    Haoran Jiang, Huandan Suo, Liwei Gao, Ye Liu, Bo Chen, Shilong Lu, Feng Jin, Yu Cao.
      This study seeks to test the effect of metformin treatment on the outcomes of breast cancer in BALB/c mice bearing 4 T1 breast cancer cells. The survival rate and tumor size of mice were compared, as well as evaluation of the changes of immune cells in spleens and the microenvironment of tumors using flow cytometry and ELISA. Our results demonstrate that metformin prolongs mouse survival. A significant decrease in M2-like macrophages (F4/80+CD206+) was found in mice spleen treated with metformin. The treatment also inhibited monocytic myeloid-derived suppressor cells (M-MDSCs, CD11b+Gr-1+) and regulatory T cells (Tregs, CD4+CD25+Foxp3+). Metformin treatment resulted in an increase in the level of IFN-γ and a decrease in IL-10. Expression of the immune checkpoint molecule PD-1 on T cells was inhibited following treatment. Metformin enhances local antitumor activity in the tumor microenvironment, and our data supports the drug as a candidate for evaluation in the treatment of breast cancer.
    Keywords:  Breast cancer; Immune checkpoint molecules; Metformin; Protective immune response
    DOI:  https://doi.org/10.1016/j.intimp.2023.110038
  19. Cells. 2023 Mar 20. pii: 939. [Epub ahead of print]12(6):
    Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts.
    Elena Andreucci, Bianca Saveria Fioretto, Irene Rosa, Marco Matucci-Cerinic, Alessio Biagioni, Eloisa Romano, Lido Calorini, Mirko Manetti.
      Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.
    Keywords:  adipocytes; adipose-derived stem cells; breast cancer cells; cancer-associated fibroblasts; cell differentiation; extracellular acidosis; lactate; myofibroblasts
    DOI:  https://doi.org/10.3390/cells12060939
  20. Front Immunol. 2023 ;14 1135086
    Neutrophil extracellular traps in tumor progression and immunotherapy.
    Meina Yan, Yifeng Gu, Hongxia Sun, Qinghong Ge.
      Tumor immunity is a growing field of research that involves immune cells within the tumor microenvironment. Neutrophil extracellular traps (NETs) are neutrophil-derived extracellular web-like chromatin structures that are composed of histones and granule proteins. Initially discovered as the predominant host defense against pathogens, NETs have attracted increasing attention due to they have also been tightly associated with tumor. Excessive NET formation has been linked to increased tumor growth, metastasis, and drug resistance. Moreover, through direct and/or indirect effects on immune cells, an abnormal increase in NETs benefits immune exclusion and inhibits T-cell mediated antitumor immune responses. In this review, we summarize the recent but rapid progress in understanding the pivotal roles of NETs in tumor and anti-tumor immunity, highlighting the most relevant challenges in the field. We believe that NETs may be a promising therapeutic target for tumor immunotherapy.
    Keywords:  anti-tumor immunity; immunotherapy; neutrophil extracellular traps; tumor microenvironment; tumor progression
    DOI:  https://doi.org/10.3389/fimmu.2023.1135086
  21. Int Immunopharmacol. 2023 Mar 27. pii: S1567-5769(23)00385-5. [Epub ahead of print]118 110064
    Methionine enkephalin suppresses lung cancer metastasis by regulating the polarization of tumor-associated macrophages and the distribution of myeloid-derived suppressor cells in the tumor microenvironment and inhibiting epithelial-mesenchymal transition.
    Shuling Zhang, Jin Geng, Fengping Shan, Yuanye Shan, Noreen Griffin, Bin Wu, Xu Wang.
      Metastasis is one of the most difficult challenges for clinical lung cancer treatment. Epithelial-mesenchymal transition (EMT) is the crucial step of tumor metastasis. Immune cells in the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), promote cancer cell EMT. In this study, we explored the effect of methionine enkephalin (MENK) on the EMT process in vitro and in vivo, and its influence on TAMs, MDSCs, and associated cytokines in vivo. The results showed that MENK suppressed growth, migration, and invasion of lung cancer cells and inhibited the EMT process by interacting with opioid growth factor receptor. MENK reduced the number of M2 macrophages and MDSC infiltration, and downregulated the expression of interleukin-10 and transforming growth factor-β1 in both primary and metastatic tumors of nude mice. The present findings suggest that MENK is a potential target for suppressing metastasis in lung cancer treatment.
    Keywords:  Epithelial-mesenchymal transition; Lung cancer; MENK; Metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2023.110064
  22. Breast Cancer Res. 2023 Mar 30. 25(1): 34
    Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low.
    Xi E Hu, Ping Yang, Songhao Chen, Gang Wei, Lijuan Yuan, Zhenyu Yang, Li Gong, Li He, Lin Yang, Shujia Peng, Yanming Dong, Xianli He, Guoqiang Bao.
      BACKGROUND: HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear.METHODS: We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2low) and 94 HER2-negtive (HER2neg) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2neg vs. HER2low, 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples.
    RESULTS: Compared with HER2neg TNBC, HER2low TNBC patients exhibited malignant clinical features with larger tumor size (P = 0.04), more lymph nodes involvement (P = 0.02), higher histological grade of lesions (P < 0.001), higher Ki67 status (P < 0.01), and a worse prognosis (P < 0.001; HR [CI 95%] = 3.44 [2.10-5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2low TNBC but not in HER2neg TNBC patients. ScRNA-seq revealed that HER2low TNBC which showed more metabolically active and aggressive hallmarks, while HER2neg TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes (IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2low and HER2neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2neg TNBC revealed a potentially more active immune microenvironment than HER2low TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8+ effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response.
    CONCLUSIONS: This study suggests that HER2low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2neg phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provide new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.
    Keywords:  HER2-low; Heterogeneity; Prognosis; Single-cell RNA sequencing; Triple-negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13058-023-01639-y
  23. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(22)00122-8. [Epub ahead of print]375 1-31
    Cancer-cell-intrinsic mechanisms regulate MDSCs through cytokine networks.
    Yuting Zhang, Sean Murphy, Xin Lu.
      Immunotherapy has shifted the paradigm of cancer treatment. However, the majority of cancer patients display de novo or acquired resistance to immunotherapy. One of the main mechanisms of immunotherapy resistance is the immunosuppressive microenvironment dominated by the myeloid-derived suppressor cells (MDSCs). Emerging evidence demonstrates that genetic or epigenetic aberrations in cancer cells shape the accumulation and activation of MDSCs. Understanding this genotype-immunophenotype relationship is critical to the rational design of combination immunotherapy. Here, we review the mechanisms of how molecular changes in cancer cells induce recruitment and reprogram the function of tumor-infiltrating myeloid cells, particularly MDSCs. Tumor-infiltrating MDSCs elicit various pro-tumor functions to promote tumor cell fitness, immune evasion, angiogenesis, tissue remodeling, and metastasis. Through understanding the genotype-immunophenotype relationship between neoplastic cells and MDSCs, new approaches can be developed to tailor current immunotherapy strategies to improve cancer patient outcomes.
    Keywords:  Cancer immunotherapy; Genotype; Immunophenotype; MDSC; Myeloid-derived suppressor cell
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.09.001
  24. J Funct Biomater. 2023 Feb 28. pii: 136. [Epub ahead of print]14(3):
    Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles.
    Shulan Han, Yongjie Chi, Zhu Yang, Juan Ma, Lianyan Wang.
      Although we have made remarkable achievements in cancer awareness and medical technology, there are still tremendous increases in cancer incidence and mortality. However, most anti-tumor strategies, including immunotherapy, show low efficiency in clinical application. More and more evidence suggest that this low efficacy may be closely related to the immunosuppression of the tumor microenvironment (TME). The TME plays a significant role in tumorigenesis, development, and metastasis. Therefore, it is necessary to regulate the TME during antitumor therapy. Several strategies are developing to regulate the TME as inhibiting tumor angiogenesis, reversing tumor associated macrophage (TAM) phenotype, removing T cell immunosuppression, and so on. Among them, nanotechnology shows great potential for delivering regulators into TME, which further enhance the antitumor therapy efficacy. Properly designed nanomaterials can carry regulators and/or therapeutic agents to eligible locations or cells to trigger specific immune response and further kill tumor cells. Specifically, the designed nanoparticles could not only directly reverse the primary TME immunosuppression, but also induce effective systemic immune response, which would prevent niche formation before metastasis and inhibit tumor recurrence. In this review, we summarized the development of nanoparticles (NPs) for anti-cancer therapy, TME regulation, and tumor metastasis inhibition. We also discussed the prospect and potential of nanocarriers for cancer therapy.
    Keywords:  antitumor therapy; microenvironment regulation; nanoparticles; tumor
    DOI:  https://doi.org/10.3390/jfb14030136
  25. Vaccines (Basel). 2023 Mar 13. pii: 644. [Epub ahead of print]11(3):
    Survivin (BIRC5) Peptide Vaccine in the 4T1 Murine Mammary Tumor Model: A Potential Neoadjuvant T Cell Immunotherapy for Triple Negative Breast Cancer: A Preliminary Study.
    Scott R Burkholz, Charles V Herst, Richard T Carback, Paul E Harris, Reid M Rubsamen.
      A triple negative breast cancer model using the murine 4T1 tumor cell line was used to explore the efficacy of an adjuvanted survivin peptide microparticle vaccine using tumor growth as the outcome metric. We first performed tumor cell dose titration studies to determine a tumor cell dose that resulted in sufficient tumor takes but allowed multiple serial measurements of tumor volumes, yet with minimal morbidity/mortality within the study period. Later, in a second cohort of mice, the survivin peptide microparticle vaccine was administered via intraperitoneal injection at the study start with a second dose given 14 days later. An orthotopic injection of 4T1 cells into the mammary tissue was performed on the same day as the administration of the second vaccine dose. The mice were followed for up to 41 days with subcutaneous measurements of tumor volume made every 3-4 days. Vaccination with survivin peptides was associated with a peptide antigen-specific gamma interferon enzyme-linked immunosorbent spot response in the murine splenocyte population but was absent from the control microparticle group. At the end of the study, we found that vaccination with adjuvanted survivin peptide microparticles resulted in statistically significant slower primary tumor growth rates in BALB/c mice challenged with 4T1 cells relative to the control peptideless vaccination group. These studies suggest that T cell immunotherapy specifically targeting survivin might be an applicable neoadjuvant immunotherapy therapy for triple negative breast cancer. More preclinical studies and clinical trials are needed to explore this concept further.
    Keywords:  BIRC5; bioinformatics; breast cancer; immunotherapy; neoadjuvant therapy; next-generation sequencing; survivin; tumor-associated antigen
    DOI:  https://doi.org/10.3390/vaccines11030644
  26. Cells. 2023 Mar 13. pii: 885. [Epub ahead of print]12(6):
    Monocyte and Macrophage in Neuroblastoma: Blocking Their Pro-Tumoral Functions and Strengthening Their Crosstalk with Natural Killer Cells.
    Chiara Vitale, Cristina Bottino, Roberta Castriconi.
      Over the past decade, immunotherapy has represented an enormous step forward in the fight against cancer. Immunotherapeutic approaches have increasingly become a fundamental part of the combined therapies currently adopted in the treatment of patients with high-risk (HR) neuroblastoma (NB). An increasing number of studies focus on the understanding of the immune landscape in NB and, since this tumor expresses low or null levels of MHC class I, on the development of new strategies aimed at enhancing innate immunity, especially Natural Killer (NK) cells and macrophages. There is growing evidence that, within the NB tumor microenvironment (TME), tumor-associated macrophages (TAMs), which mainly present an M2-like phenotype, have a crucial role in mediating NB development and immune evasion, and they have been correlated to poor clinical outcomes. Importantly, TAM can also impair the antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells upon the administration of anti-GD2 monoclonal antibodies (mAbs), the current standard immunotherapy for HR-NB patients. This review deals with the main mechanisms regulating the crosstalk among NB cells and TAMs or other cellular components of the TME, which support tumor development and induce drug resistance. Furthermore, we will address the most recent strategies aimed at limiting the number of pro-tumoral macrophages within the TME, reprogramming the TAMs functional state, thus enhancing NK cell functions. We also prospectively discuss new or unexplored aspects of human macrophage heterogeneity.
    Keywords:  IL-18; macrophages; natural killer cells; neuroblastoma
    DOI:  https://doi.org/10.3390/cells12060885
  27. Cancers (Basel). 2023 Mar 20. pii: 1860. [Epub ahead of print]15(6):
    Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases.
    Cristina L Cotarelo, Arno Schad, Marcus Schmidt, Arnd Hönig, Jonathan P Sleeman, Sonja Thaler.
      Oncogene-induced senescence is thought to constitute a barrier to carcinogenesis by arresting cells at risk of malignant transformation. However, numerous findings suggest that senescent cells may conversely promote tumor growth and metastatic progression, for example, through the senescence-associated secretory phenotype (SASP) they produce. Here, we investigated the degree to which senescent tumor cells exist within untreated human primary breast carcinomas and whether the presence of senescent cancer cells in primary tumors is recapitulated in their matched lymph node metastases. For the detection of senescence, we used SA-β-galactosidase (SA-β-gal) staining and other senescence markers such as Ki67, p21, p53, and p16. In patients with invasive luminal A and B breast carcinomas, we found broad similarities in the appearance of cancer cells between primary tumors and their corresponding metastases. Analysis of lymph nodes from patients with other breast cancer subtypes also revealed senescent tumor cells within metastatic lesions. Collectively, our findings show that senescent tumor cells exist within primary breast carcinomas and metastatic lesions. These results suggest a potential role for senescent breast tumor cells during metastatic progression and raise the question as to whether the targeting of senescent tumor cells with anti-senescent drugs might represent a novel avenue for improved treatment of breast and other cancers.
    Keywords:  cellular senescence; metastatic breast cancer; senescent breast cancer cells
    DOI:  https://doi.org/10.3390/cancers15061860
  28. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00003-5. [Epub ahead of print]376 121-141
    Fatty acid metabolism and radiation-induced anti-tumor immunity.
    Mara De Martino, Camille Daviaud, Edgar Hajjar, Claire Vanpouille-Box.
      Fatty acid metabolic reprogramming has emerged as a major regulator of anti-tumor immune responses with large body of evidence that demonstrate its ability to impact the differentiation and function of immune cells. Therefore, depending on the metabolic cues that stem in the tumor microenvironment, the tumor fatty acid metabolism can tilt the balance of inflammatory signals to either promote or impair anti-tumor immune responses. Oxidative stressors such as reactive oxygen species generated from radiation therapy can rewire the tumor energy supply, suggesting that radiation therapy can further perturb the energy metabolism of a tumor by promoting fatty acid production. In this review, we critically discuss the network of fatty acid metabolism and how it regulates immune response especially in the context of radiation therapy.
    Keywords:  Fatty acid metabolism; Immunostimulation; Immunosuppression; Nucleic acid sensing; Radiation therapy; Radioresistance
    DOI:  https://doi.org/10.1016/bs.ircmb.2023.01.003
  29. Front Immunol. 2023 ;14 1094823
    The role of Th-17 cells and IL-17 in the metastatic spread of breast cancer: As a means of prognosis and therapeutic target.
    Tewodros Shibabaw, Banchamlak Teferi, Birhanu Ayelign.
      Metastatic breast cancer is one of the most common and well-known causes of death for women worldwide. The inflammatory tumor cell and other cancer hallmarks dictate the metastatic form and dissemination of breast cancer. Taking these into account, from various components of the tumor microenvironment, a pro-inflammatory infiltrative cell known as Th-17 plays an immense role in breast cancer proliferation, invasiveness, and metastasis. It has been demonstrated that IL-17, a pleiotropic pro-inflammatory cytokine generated by Th-17, is upregulated in a metastatic form of breast cancer. Recent research updates stated that chronic inflammation and mediators like cytokines and chemokines are causative hallmarks in many human cancers, including breast cancer. Therefore, IL-17 and its multiple downward signaling molecules are the centers of research attention to develop potent treatment options for cancer. They provide information on the role of IL-17-activated MAPK, which results in tumor cell proliferation and metastasis via NF-kB-mediated expression of MMP signaling. Overall, this review article emphasizes IL-17A and its intermediate signaling molecules, such as ERK1/2, NF-kB, MMPs, and VEGF, as potential molecular targets for the prevention and treatment of breast cancer.
    Keywords:  MAPK; MMPs; NF-kB; antitumor effects; bone metastasis; breast cancer; inflammation; interleukin-17A
    DOI:  https://doi.org/10.3389/fimmu.2023.1094823
  30. Curr Oncol. 2023 Feb 22. 30(3): 2625-2641
    Tumor-Infiltrating Immune Cell Landscapes in the Lymph Node Metastasis of Papillary Thyroid Cancer.
    Md Amanullah, Meidie Pan, Kaining Lu, Xiaoqing Pan, Yan Lu, Dingcun Luo, Pengyuan Liu.
      Regional lymph node metastasis (LNM) increases the risk of distant metastasis in papillary thyroid cancer (PTC) patients. However, it remains unclear how tumor cells in PTC patients with LNM evade immune system surveillance and proceed to colonize distant organs. Here, we comprehensively characterize the tumor-infiltrating immune cell landscape in PTC with LNM. LNM-related genes include multiple important soluble mediators such as CXCL6, IL37, MMP10, and COL11A1, along with genes involved in areas such as extracellular matrix organization and TLR regulation by endogenous ligands. In PTC without LNM, the tumor infiltration of activated dendritic cells and M0 macrophages showed increases from normal cells, but with yet greater increases and correspondingly worse prognosis in PTC with LNM. Conversely, the tumor infiltration of activated NK cells and eosinophils was decreased in PTC without LNM, as compared to normal cells, and yet further decreased in PTC with LNM, with such decreases associated with poor prognosis. We further demonstrate that mutations of driver genes in tumor cells influence the infiltration of surrounding immune cells in the tumor microenvironment (TME). Particularly, patients carrying TG mutations tend to show increased filtration of M2 macrophages and activated NK cells in the TME, whereas patients carrying HRAS mutations tend to show reduced filtration of M0 macrophages and show enhanced filtration of activated dendritic cells in the TME. These findings increase our understanding of the mechanisms of regional lymph node metastasis in PTC and its associated tumor microenvironment, potentially facilitating the development of personalized treatment regimens to combat immunotherapy failure.
    Keywords:  driver mutation; immune cells; lymph node metastasis; prognosis; thyroid cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/curroncol30030200
  31. bioRxiv. 2023 Mar 23. pii: 2023.03.20.533534. [Epub ahead of print]
    Overexpressed Malat1 Drives Metastasis through Inflammatory Reprogramming of Lung Adenocarcinoma Microenvironment.
    Elena Mart Nez-Terroba, Fernando J de Miguel, Vincent Li, Camila Robles-Oteiza, Katerina Politi, Jesse R Zamudio, Nadya Dimitrova.
      Metastasis is the main cause of cancer deaths but the molecular events leading to metastatic dissemination remain incompletely understood. Despite reports linking aberrant expression of long noncoding RNAs (lncRNAs) with increased metastatic incidence , in vivo evidence establishing driver roles for lncRNAs in metastatic progression is lacking. Here, we report that overexpression of the metastasis-associated lncRNA Malat1 (metastasis-associated lung adenocarcinoma transcript 1) in the autochthonous K-ras/p53 mouse model of lung adenocarcinoma (LUAD) is sufficient to drive cancer progression and metastatic dissemination. We show that increased expression of endogenous Malat1 RNA cooperates with p53 loss to promote widespread LUAD progression to a poorly differentiated, invasive, and metastatic disease. Mechanistically, we observe that Malat1 overexpression leads to the inappropriate transcription and paracrine secretion of the inflammatory cytokine, Ccl2, to augment the mobility of tumor and stromal cells in vitro and to trigger inflammatory responses in the tumor microenvironment in vivo . Notably, Ccl2 blockade fully reverses cellular and organismal phenotypes of Malat1 overexpression. We propose that Malat1 overexpression in advanced tumors activates Ccl2 signaling to reprogram the tumor microenvironment to an inflammatory and pro-metastatic state.
    DOI:  https://doi.org/10.1101/2023.03.20.533534
  32. Cancers (Basel). 2023 Mar 08. pii: 1650. [Epub ahead of print]15(6):
    Role and Potential of Different T Helper Cell Subsets in Adoptive Cell Therapy.
    David Andreu-Sanz, Sebastian Kobold.
      Historically, CD8+ T cells have been considered the most relevant effector cells involved in the immune response against tumors and have therefore been the focus of most cancer immunotherapy approaches. However, CD4+ T cells and their secreted factors also play a crucial role in the tumor microenvironment and can orchestrate both pro- and antitumoral immune responses. Depending on the cytokine milieu to which they are exposed, CD4+ T cells can differentiate into several phenotypically different subsets with very divergent effects on tumor progression. In this review, we provide an overview of the current knowledge about the role of the different T helper subsets in the immune system, with special emphasis on their implication in antitumoral immune responses. Furthermore, we also summarize therapeutic applications of each subset and its associated cytokines in the adoptive cell therapy of cancer.
    Keywords:  CD4+ T cell; adoptive cell therapy; cytokines; immunotherapy
    DOI:  https://doi.org/10.3390/cancers15061650
  33. Int J Mol Sci. 2023 Mar 07. pii: 5115. [Epub ahead of print]24(6):
    Differential Transcriptome Responses in Human THP-1 Macrophages Following Exposure to T98G and LN-18 Human Glioblastoma Secretions: A Simplified Bioinformatics Approach to Understanding Patient-Glioma-Specific Effects on Tumor-Associated Macrophages.
    Micaela R Scobie, Abdullah Abood, Charles D Rice.
      A common theme in glioma disease progression is robust infiltration of immune cells within the tumor microenvironment, resulting in a state of chronic inflammation. This disease state is characterized by an abundance of CD68+ microglia and CD163+ bone marrow-derived macrophages with the greater the percentage of CD163+ cells, the poorer the prognosis. These macrophages are "cold," in that their phenotype is of an alternatively activated state (M0-M2-like) supporting tumor growth rather than being engaged with classically activated, pro-inflammatory, and anti-tumor activities, referred to as "hot", or M1-like. Herein, we have developed an in vitro approach that uses two human glioma cell lines, T98G and LN-18, which exhibit a variety of differing mutations and characteristics, to demonstrate their disparate effects on differentiated THP-1 macrophages. We first developed an approach to differentiating THP-1 monocytes to macrophages with mixed transcriptomic phenotypes we regard as M0-like macrophages. We then found that supernatants from the two different glioma cell lines induced different gene expression profiles in THP-1 macrophages, suggesting that from patient to patient, gliomas may be considered as different diseases. This study suggests that in addition to standard glioma treatment modalities, transcriptome profiling of the effects of cultured glioma cells on a standard THP-1 macrophage in vitro model may lead to future druggable targets that aim to reprogram tumor-associated macrophages towards an anti-tumor phenotype.
    Keywords:  LN-18 glioma; T98G glioma; THP-1 macrophage; transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms24065115
  34. Cancers (Basel). 2023 Mar 18. pii: 1836. [Epub ahead of print]15(6):
    Inflammation, Infiltration, and Evasion-Tumor Promotion in the Aging Breast.
    Nicole Cruz-Reyes, Derek C Radisky.
      Breast cancer is a significant cause of morbidity and mortality in women, with over two million new cases reported worldwide each year, the majority of which occur in post-menopausal women. Despite advances in early detection and treatment, approximately one-third of patients diagnosed with breast cancer will develop metastatic disease. The pathogenesis and progression of breast cancer are influenced by a variety of biological and social risk factors, including age, ethnicity, pregnancy status, diet, and genomic alterations. Recent advancements in breast cancer research have focused on harnessing the power of the patient's adaptive and innate immune systems for diagnostic and therapeutic purposes. The breast immune microenvironment plays a critical role in regulating tissue homeostasis and resistance to tumorigenesis. In this review, we explore the dynamic changes in the breast immune microenvironment that occur with age, how these changes impact breast cancer development and progression, and how targeted therapeutic interventions that leverage the immune system can be used to improve patient outcomes. Our review emphasizes the importance of understanding the complex interplay between aging, the immune system, and breast cancer, and highlights the potential of immune-based therapies in the fight against this devastating disease.
    Keywords:  aging; breast cancer; immune system; immunoediting
    DOI:  https://doi.org/10.3390/cancers15061836
  35. Int J Mol Sci. 2023 Mar 14. pii: 5512. [Epub ahead of print]24(6):
    Tamoxifen Modulates the Immune Landscape of the Tumour Microenvironment: The Paired Siglec-5/14 Checkpoint in Anti-Tumour Immunity in an In Vitro Model of Breast Cancer.
    Przemyslaw Wielgat, Karol Rogowski, Robert Czarnomysy, Natalia Wawrusiewicz-Kurylonek, Karolina Narejko, Krzysztof Bielawski, Halina Car.
      Since the role of sialome-Siglec axis has been described as a regulatory checkpoint of immune homeostasis, the promotion of stimulatory or inhibitory Siglec-related mechanisms is crucial in cancer progression and therapy. Here, we investigated the effect of tamoxifen on the sialic acid-Siglec interplay and its significance in immune conversion in breast cancer. To mimic the tumour microenvironment, we used oestrogen-dependent or oestrogen-independent breast cancer cells/THP-1 monocytes transwell co-cultures exposed to tamoxifen and/or β-estradiol. We found changes in the cytokine profiles accompanied by immune phenotype switching, as measured by the expression of arginase-1. The immunomodulatory effects of tamoxifen in THP-1 cells occurred with the altered SIGLEC5 and SIGLEC14 genes and the expression of their products, as confirmed by RT-PCR and flow cytometry. Additionally, exposure to tamoxifen increased the binding of Siglec-5 and Siglec-14 fusion proteins to breast cancer cells; however, these effects appeared to be unassociated with oestrogen dependency. Our results suggest that tamoxifen-induced alterations in the immune activity of breast cancer reflect a crosstalk between the Siglec-expressing cells and the tumour's sialome. Given the distribution of Siglec-5/14, the expression profile of inhibitory and activatory Siglecs in breast cancer patients may be useful in the verification of therapeutic strategies and predicting the tumour's behaviour and the patient's overall survival.
    Keywords:  Siglec; breast cancer; microenvironment; monocytes; tamoxifen
    DOI:  https://doi.org/10.3390/ijms24065512
  36. Nat Rev Cancer. 2023 Mar 27.
    Nucleotide metabolism: a pan-cancer metabolic dependency.
    Nicholas J Mullen, Pankaj K Singh.
      Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.
    DOI:  https://doi.org/10.1038/s41568-023-00557-7
  37. Cell Death Discov. 2023 Mar 25. 9(1): 103
    The effects of MYC on tumor immunity and immunotherapy.
    Jiajin Li, Tingyu Dong, Zhen Wu, Dacheng Zhu, Hao Gu.
      The oncogene MYC is dysregulated in a host of human cancers, and as an important point of convergence in multitudinous oncogenic signaling pathways, it plays a crucial role in tumor immune regulation in the tumor immune microenvironment (TIME). Specifically, MYC promotes the expression of immunosuppressive factors and inhibits the expression of immune activation regulators. Undoubtedly, a therapeutic strategy that targets MYC can initiate a new era of cancer treatment. In this review, we summarize the essential role of the MYC signaling pathway in tumor immunity and the development status of MYC-related therapies, including therapeutic strategies targeting MYC and combined MYC-based immunotherapy. These studies have reported extraordinary insights into the translational application of MYC in cancer treatment and are conducive to the emergence of more effective immunotherapies for cancer.
    DOI:  https://doi.org/10.1038/s41420-023-01403-3
  38. Metabolites. 2023 Feb 25. pii: 345. [Epub ahead of print]13(3):
    The Role of Reprogrammed Glucose Metabolism in Cancer.
    Meran Keshawa Ediriweera, Sharmila Jayasena.
      Cancer cells reprogram their metabolism to meet biosynthetic needs and to adapt to various microenvironments. Accelerated glycolysis offers proliferative benefits for malignant cells by generating glycolytic products that move into branched pathways to synthesize proteins, fatty acids, nucleotides, and lipids. Notably, reprogrammed glucose metabolism and its associated events support the hallmark features of cancer such as sustained cell proliferation, hijacked apoptosis, invasion, metastasis, and angiogenesis. Overproduced enzymes involved in the committed steps of glycolysis (hexokinase, phosphofructokinase-1, and pyruvate kinase) are promising pharmacological targets for cancer therapeutics. In this review, we summarize the role of reprogrammed glucose metabolism in cancer cells and how it can be manipulated for anti-cancer strategies.
    Keywords:  cancer; cancer treatment; glucose; metabolism
    DOI:  https://doi.org/10.3390/metabo13030345
  39. Eur J Pharmacol. 2023 Mar 27. pii: S0014-2999(23)00189-9. [Epub ahead of print] 175678
    TGF-β signaling pathway: Therapeutic targeting and potential for anti-cancer immunity.
    Shafat Ali, Muneeb U Rehman, Ali Mohd Yatoo, Azher Arafah, Andleeb Khan, Summya Rashid, Sabhiya Majid, Aarif Ali, Md Niamat Ali.
      Transforming growth factor-β (TGFβ) is a pleiotropic secretory cytokine exhibiting both cancer-inhibitory and promoting properties. It transmits its signals via Suppressor of Mother against Decapentaplegic (SMAD) and non-SMAD pathways and regulates cell proliferation, differentiation, invasion, migration, and apoptosis. In non-cancer and early-stage cancer cells, TGFβ signaling suppresses cancer progression via inducing apoptosis, cell cycle arrest, or anti-proliferation, and promoting cell differentiation. On the other hand, TGFβ may also act as an oncogene in advanced stages of tumors, wherein it develops immune-suppressive tumor microenvironments and induces the proliferation of cancer cells, invasion, angiogenesis, tumorigenesis, and metastasis. Higher TGFβ expression leads to the instigation and development of cancer. Therefore, suppressing TGFβ signals may present a potential treatment option for inhibiting tumorigenesis and metastasis. Different inhibitory molecules, including ligand traps, anti-sense oligo-nucleotides, small molecule receptor-kinase inhibitors, small molecule inhibitors, and vaccines, have been developed and clinically trialed for blocking the TGFβ signaling pathway. These molecules are not pro-oncogenic response-specific but block all signaling effects induced by TGFβ. Nonetheless, targeting the activation of TGFβ signaling with maximized specificity and minimized toxicity can enhance the efficacy of therapeutic approaches against this signaling pathway. The molecules that are used to target TGFβ are non-cytotoxic to cancer cells but designed to curtail the over-activation of invasion and metastasis driving TGFβ signaling in stromal and cancer cells. Here, we discussed the critical role of TGFβ in tumorigenesis, and metastasis, as well as the outcome and the promising achievement of TGFβ inhibitory molecules in the treatment of cancer.
    Keywords:  Anti-sense oligonucleotides; Antibodies; Immune-suppression; Kinase-inhibitors; TGFβ; Tumor microenvironment; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175678
  40. Pharmacology. 2023 Mar 30. 1-12
    Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas.
    Giulia Toffanin, Andrej Ozaniak, Robin Bartolini, Martin Komarc, Rene Novysedlak, Michal Rataj, Jitka Smetanova, Antonio Rosato, Robert Lischke, Jirina Bartunkova, Zuzana Strizova.
      INTRODUCTION: Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far.METHODS: The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies.
    RESULTS: The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma.
    CONCLUSION: In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.
    Keywords:  Cytokines; Monoclonal antibody; Nivolumab; Oncostatin M; Soft tissue sarcomas; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1159/000529811
  41. PLoS One. 2023 ;18(3): e0283003
    GATA-3 expression in breast cancer is related to intratumoral M2 macrophage infiltration and tumor differentiation.
    Husam Oda, Elham Hedayati, Annelie Lindström, Ivan Shabo.
      Accumulating evidence indicates that tumor-associated macrophages promote tumor progression and that high macrophage infiltration is correlated with advanced tumor stages and poor prognosis in breast cancer. GATA binding protein 3 (GATA-3) is a differentiation marker related to differentiated states in breast cancer. In this study, we explore how the extent of MI relates to GATA-3 expression, hormonal status, and the differentiation grade of breast cancer. To examine breast cancer in early development, we selected 83 patients that were treated with radical breast-conserving surgery (R0), without lymph node metastases (N0) or distant metastases (M0), with and without postoperative radiotherapy. Immunostaining of M2-macrophage-specific antigen CD163 was used to detect tumor-associated macrophages, and macrophage infiltration was estimated semi-quantitatively into no/low, moderate, and high infiltration. The macrophage infiltration was compared to GATA-3, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 expression in cancer cells. GATA-3 expression is associated with ER and PR expression but inversely correlated to macrophage infiltration and Nottingham histologic grade. High macrophage infiltration in advanced tumor grade was associated with low GATA-3 expression. The disease-free survival is inversely related to Nottingham histologic grade in patients having tumors with no/low macrophage infiltration, a difference that is not found in patients with moderate/high macrophage infiltration. These findings indicate that macrophage infiltration might impact the differentiation, malignant behavior, and prognosis of breast cancer, regardless of the morphological and hormonal states of the cancer cells in the primary tumor.
    DOI:  https://doi.org/10.1371/journal.pone.0283003
  42. J Pers Med. 2023 Feb 28. pii: 457. [Epub ahead of print]13(3):
    Cytotoxic Lymphocyte-Related Gene Signature in Triple-Negative Breast Cancer.
    Yiqun Han, Jiayu Wang, Binghe Xu.
      To curate the signature genes of cytotoxic lymphocytes (CLs) and explore the heterogeneity based on the CL-related (CLR) gene signature, we analyzed the gene expression of 592 patients with histologically diagnosed triple-negative breast cancer. Based on the 13-gene panel, CLR signatures were curated and associated with the stage of tumor size. Patients in the CLR-low group exhibited the worse overall survival (OS) (median OS, 75.23 months vs. 292.66 months, p < 0.0001) and were characterized by the upregulation of the NF-κB, Wnt, and p53 pathways, the positive regulation of angiogenesis, and a higher expression of immune checkpoints including CTLA4, LAG3, CD86, ICOS, ICOSLG, and TNFSF9. In cancer immunotherapy cohorts (GSE157284, GSE35640, IMvigor210), a higher CLR signature score was remarkably associated with greater tumor shrinkage and immune characteristics consisting of higher PD-L1 and neoantigen expression, as well as an inflamed tumor microenvironment. In the pan-cancer atlas, the CLR signature was notably associated with patient survival and revealed a profound heterogeneity across the malignancy types. In sum, the CLR signature is a promising indicator for immune characteristics, tumor shrinkage, and survival outcomes following cancer immunotherapy in addition to the prognostic heterogeneity in the pan-cancer atlas.
    Keywords:  breast cancer; cancer immunotherapy; cytotoxic lymphocytes; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3390/jpm13030457
  43. Front Immunol. 2023 ;14 1121565
    Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes.
    Priyanka Maridhi Nanjireddy, Scott H Olejniczak, Nataliya Prokopenko Buxbaum.
      Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies.
    Keywords:  CAR T cell; adoptive cell therapy (ACT); cell metabolism; immunometabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1121565
  44. Cancer Res Commun. 2023 Jan;3(1): 80-96
    IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines.
    Van Anh Do-Thi, Sang Min Park, Song Mi Park, Hye Jin Jeong, Geunyoung Cho, Hyun-Jung An, Young Sang Kim, Hayyoung Lee, Jie-Oh Lee.
      Tumor-associated macrophages (TAM) are involved in tumor progression, metastasis, and immunosuppression. Because TAMs are highly plastic and could alter their phenotypes to proinflammatory M1 in response to environmental stimuli, reeducating TAMs has emerged as a promising approach to overcoming the challenges of solid cancer treatment. This study investigated the effect of IL9 on macrophage M1 polarization and verified its antitumor potential to retrain TAMs and promote chemokine secretion. We demonstrated that IL9 stimulated macrophage proliferation and polarized them toward the proinflammatory M1 phenotype in an IFNγ-dependent manner. Tumor-localized IL9 also polarized TAMs toward M1 in vivo and made them release CCL3/4 and CXCL9/10 to recruit antitumor immune cells, including T and natural killer cells, into the tumor microenvironment. Furthermore, peritoneal treatment with recombinant IL9 delayed the growth of macrophage-enriched B16F10 melanoma and 4T1 breast cancer in syngeneic mice, although IL9 treatment did not reduce tumor growth in the absence of macrophage enrichment. These results demonstrate the efficacy of IL9 in macrophage polarization to trigger antitumor immunity.Significance: These findings clarified the effect of IL9 on macrophage M1 polarization and verified its antitumor potential through retraining TAMs and chemokine secretion.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0246
  45. Biomark Res. 2023 Mar 29. 11(1): 34
    Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies.
    Shifen Wang, Xingyun Zhao, Siwen Wu, Dawei Cui, Zhenshu Xu.
      The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits tumor immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity and mortality worldwide. As an important component of immunosuppressive regulators, the phenotypic characteristics and prognostic value of myeloid-derived suppressor cells (MDSCs) have received much attention. A variety of MDSC-targeting therapeutic approaches have produced encouraging outcomes. However, the use of various MDSC-targeted treatment strategies in hematologic malignancies is still difficult due to the heterogeneity of hematologic malignancies and the complexity of the immune system. In this review, we summarize the biological functions of MDSCs and further provide a summary of the phenotypes and suppressive mechanisms of MDSC populations expanded in various types of hematological malignancy contexts. Moreover, we discussed the clinical correlation between MDSCs and the diagnosis of malignant hematological disease, as well as the drugs targeting MDSCs, and focused on summarizing the therapeutic strategies in combination with other immunotherapies, such as various immune checkpoint inhibitors (ICIs), that are under active investigation. We highlight the new direction of targeting MDSCs to improve the therapeutic efficacy of tumors.
    Keywords:  Hematological malignancies; Immunosuppressive regulator; Immunotherapy; Myeloid-derived suppressor cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40364-023-00475-8
  46. Semin Immunol. 2023 Mar 27. pii: S1044-5323(23)00030-1. [Epub ahead of print]67 101739
    TREM2: A new player in the tumor microenvironment.
    Martina Molgora, Yizhou A Liu, Marco Colonna, Marina Cella.
      TREM2 is a myeloid cell receptor that has been extensively described in the context of neuroinflammation and neurodegenerative diseases. Recently, TREM2 emerged as a crucial regulator of macrophage function in tumors. TREM2-deficiency or blockade provide protection and promote the response to anti-PD1 in different murine models. In human tumors, TREM2-expressing macrophages are present in numerous cohorts and tumor types and are generally associated with immunosuppression and poor prognosis. Here, we provide an overview of the impact of TREM2 in tumors considering current literature, with a focus on both murine models and human cancer.
    Keywords:  Cancer; Immunotherapy; Macrophages; TREM2
    DOI:  https://doi.org/10.1016/j.smim.2023.101739
  47. Antioxid Redox Signal. 2023 Apr 01.
    Redox dysregulation in the tumor microenvironment contributes to cancer metastasis.
    Wanning Liu, Boda Wang, Mingzhen Zhou, Dan Liu, Fulin Chen, Xiaodi Zhao, Yuanyuan Lu.
      SIGNIFICANCE: Redox dysregulation under pathological conditions results in excessive reactive oxygen species (ROS) accumulation, leading to oxidative stress and cellular oxidative damage. ROS function as a double-edged sword to modulate various types of cancer development and survival.RECENT ADVANCES: Emerging evidence has underlined that ROS impact the behavior of both cancer cells and tumor-associated stromal cells in the tumor microenvironment (TME), and these cells have developed complex systems to adapt to high ROS environments during cancer progression.
    CRITICAL ISSUES: In this review, we integrated current progress regarding the impact of ROS on cancer cells and tumor-associated stromal cells in the TME and summarized how ROS production influences cancer cell behaviors. Then, we summarized the distinct effects of ROS during different stages of tumor metastasis. Finally, we discussed potential therapeutic strategies for modulating ROS for the treatment of cancer metastasis.
    FUTURE DIRECTIONS: Targeting the ROS regulation during cancer metastasis will provide important insights into the design of effective single or combinatorial cancer therapeutic strategies. Well-designed preclinical studies and clinical trials are urgently needed to understand the complex regulatory systems of ROS in the TME.
    DOI:  https://doi.org/10.1089/ars.2023.0272
  48. Int J Mol Sci. 2023 Mar 07. pii: 5086. [Epub ahead of print]24(6):
    Role of Heterogeneous Nuclear Ribonucleoproteins in the Cancer-Immune Landscape.
    Meenakshi Sudhakaran, Andrea I Doseff.
      Cancer remains the second leading cause of death, accounting for approximately 20% of all fatalities. Evolving cancer cells and a dysregulated immune system create complex tumor environments that fuel tumor growth, metastasis, and resistance. Over the past decades, significant progress in deciphering cancer cell behavior and recognizing the immune system as a hallmark of tumorigenesis has been achieved. However, the underlying mechanisms controlling the evolving cancer-immune landscape remain mostly unexplored. Heterogeneous nuclear ribonuclear proteins (hnRNP), a highly conserved family of RNA-binding proteins, have vital roles in critical cellular processes, including transcription, post-transcriptional modifications, and translation. Dysregulation of hnRNP is a critical contributor to cancer development and resistance. HnRNP contribute to the diversity of tumor and immune-associated aberrant proteomes by controlling alternative splicing and translation. They can also promote cancer-associated gene expression by regulating transcription factors, binding to DNA directly, or promoting chromatin remodeling. HnRNP are emerging as newly recognized mRNA readers. Here, we review the roles of hnRNP as regulators of the cancer-immune landscape. Dissecting the molecular functions of hnRNP will provide a better understanding of cancer-immune biology and will impact the development of new approaches to control and treat cancer.
    Keywords:  apoptosis; cancer resistance; immune regulation; macrophages; myeloid
    DOI:  https://doi.org/10.3390/ijms24065086
  49. Biomedicines. 2023 Mar 17. pii: 934. [Epub ahead of print]11(3):
    Exploring the Role of Hypoxia-Inducible Carbonic Anhydrase IX (CAIX) in Circulating Tumor Cells (CTCs) of Breast Cancer.
    Julianne D Twomey, Baolin Zhang.
      Circulating tumor cells (CTCs) in the peripheral blood are believed to be the source of metastasis and can be used as a liquid biopsy to monitor cancer progression and therapeutic response. However, it has been challenging to accurately detect CTCs because of their low frequency and the heterogeneity of the population. In this study, we have developed an in vitro model of CTCs by using non-adherent suspension culture. We used this model to study a group of breast cancer cell lines with distinct molecular subtypes (TNBC, HER2+, and ER+/PR+). We found that, when these breast cancer cell lines lost their attachment to the extracellular matrix, they accumulated a subtype of cancer stem cells (CSC) that expressed the surface markers of stem cells (e.g., CD44+CD24-). These stem-like CTCs also showed high expressions of hypoxia-inducible gene products, particularly the hypoxia-inducible carbonic anhydrase IX (CAIX). Inhibition of CAIX activity was found to reduce CAIX expression and stem cell phenotypes in the targeted CTCs. Further studies are needed, using CTC samples from breast cancer patients, to determine the role of CAIX in CTC survival, CSC transition, and metastasis. CAIX may be a useful surface marker for the detection of CSCs in the blood, and a potential target for treating metastatic breast cancers.
    Keywords:  biomarker; breast cancer; cancer stem cells (CSC); cancer therapy; circulating tumor cells (CTCs); liquid biopsy; metastasis; molecular profile
    DOI:  https://doi.org/10.3390/biomedicines11030934
  50. Nature. 2023 Mar 29.
    STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.
    Jing Hu, Francisco J Sánchez-Rivera, Zhenghan Wang, Gabriela N Johnson, Yu-Jui Ho, Karuna Ganesh, Shigeaki Umeda, Siting Gan, Adriana M Mujal, Rebecca B Delconte, Jessica P Hampton, Huiyong Zhao, Sanjay Kottapalli, Elisa de Stanchina, Christine A Iacobuzio-Donahue, Dana Pe'er, Scott W Lowe, Joseph C Sun, Joan Massagué.
      Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.
    DOI:  https://doi.org/10.1038/s41586-023-05880-5
  51. Front Immunol. 2023 ;14 1164514
    Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer.
    Bi Lian, Xiaosong Chen, Kunwei Shen.
      Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs via mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.
    Keywords:  HDAC; breast cancer; immunotherapy; inhibitors; targets
    DOI:  https://doi.org/10.3389/fimmu.2023.1164514
  52. Cancer Res Commun. 2022 Nov;2(11): 1404-1417
    CD47-blocking Antibody ZL-1201 Promotes Tumor-associated Macrophage Phagocytic Activity and Enhances the Efficacy of the Therapeutic Antibodies and Chemotherapy.
    Anthony Cao, Jiaqing Yi, Xinyan Tang, Christopher W Szeto, Renyi Wu, Bing Wan, Xu Fang, Shou Li, Lei Wang, Lina Wang, Jing Li, Qiuping Ye, Tom Huang, Karl Hsu, Omar Kabbarah, Haiying Zhou.
      Tumor-associated macrophages (TAM) are the most abundant immune cells in the tumor microenvironment. They consist of various subsets but primarily resemble the M2 macrophage phenotype. TAMs are known to promote tumor progression and are associated with poor clinical outcomes. CD47 on tumor cells and SIRPα on TAMs facilitate a "don't-eat-me" signal which prevents cancer cells from immune clearance. Therefore, blockade of the CD47-SIRPα interaction represents a promising strategy for tumor immunotherapy. Here, we present the results on ZL-1201, a differentiated and potent anti-CD47 antibody with improved hematologic safety profile compared with 5F9 benchmark. ZL-1201 enhanced phagocytosis in combination with standards of care (SoC) therapeutic antibodies in in vitro coculture systems using a panel of tumor models and differentiated macrophages, and these combinational effects are Fc dependent while potently enhancing M2 phagocytosis. In vivo xenograft studies showed that enhanced antitumor activities were seen in a variety of tumor models treated with ZL-1201 in combination with other therapeutic mAbs, and maximal antitumor activities were achieved in the presence of chemotherapy in addition to the combination of ZL-1201 with other mAbs. Moreover, tumor-infiltrating immune cells and cytokine analysis showed that ZL-1201 and chemotherapies remodel the tumor microenvironment, which increases antitumor immunity, leading to augmented antitumor efficacy when combined with mAbs.Significance: ZL-1201 is a novel anti-CD47 antibody that has improved hematologic safety profiles and combines with SoC, including mAbs and chemotherapies, to potently facilitate phagocytosis and antitumor efficacy.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0266
  53. J Immunol. 2023 Mar 31. pii: ji2200897. [Epub ahead of print]
    IL-12 and IL-27 Promote CD39 Expression on CD8+ T Cells and Differentially Regulate the CD39+CD8+ T Cell Phenotype.
    Lara Gerhardt, Megan M Y Hong, Yeganeh Yousefi, Rene Figueredo, Saman Maleki Vareki.
      Tumor-specific CD8+ T cells are critical components of antitumor immunity; however, factors that modulate their phenotype and function have not been completely elucidated. Cytokines IL-12 and IL-27 have recognized roles in promoting CD8+ T cells' effector function and mediated antitumor responses. Tumor-specific CD8+ tumor-infiltrating lymphocytes (TILs) can be identified based on surface expression of CD39, whereas bystander CD8+ TILs do not express this enzyme. It is currently unclear how and why tumor-specific CD8+ T cells uniquely express CD39. Given the important roles of IL-12 and IL-27 in promoting CD8+ T cell functionality, we investigated whether these cytokines could modulate CD39 expression on these cells. Using in vitro stimulation assays, we identified that murine splenic CD8+ T cells differentially upregulate CD39 in the presence of IL-12 and IL-27. Subsequently, we assessed the exhaustion profile of IL-12- and IL-27-induced CD39+CD8+ T cells. Despite the greatest frequency of exhausted CD39+CD8+ T cells after activation with IL-12, as demonstrated by the coexpression of TIM-3+PD-1+LAG-3+ and reduced degranulation capacity, these cells retained the ability to produce IFN-γ. IL-27-induced CD39+CD8+ T cells expressed PD-1 but did not exhibit a terminally exhausted phenotype. IL-27 was able to attenuate IL-12-mediated inhibitory receptor expression on CD39+CD8+ T cells but did not rescue degranulation ability. Using an immunogenic neuro-2a mouse model, inhibiting IL-12 activity reduced CD39+CD8+ TIL frequency compared with controls without changing the overall CD8+ TIL frequency. These results provide insight into immune regulators of CD39 expression on CD8+ T cells and further highlight the differential impact of CD39-inducing factors on the phenotype and effector functions of CD8+ T cells.
    DOI:  https://doi.org/10.4049/jimmunol.2200897
  54. Front Pharmacol. 2023 ;14 1092767
    Pexidartinib synergize PD-1 antibody through inhibiting treg infiltration by reducing TAM-derived CCL22 in lung adenocarcinoma.
    Wei Zhang, Xi Jiang, Youcheng Zou, Lihua Yuan, Xiaobo Wang.
      There is a crosstalk between Tumor-associated macrophages (TAM) and tumor-infiltrating T cells in tumor environment. TAM could inhibit the activity of cytotoxic T cells; TAM could also regulate the composition of T cells in tumor immune environment. The combination therapy for TAM and tumor infiltrated T cells has been widely noticed, but the crosstalk between TAM and tumor infiltrated T cells remains unclear in the process of combination therapy. We treated lung adenocarcinoma tumor models with pexidartinib, which targets macrophage colony stimulating factor receptor (M-CSFR) and c-kit tyrosine kinase, to inhibited TAM. Pexidartinib inhibited the ratio of macrophages in the tumor and also altered macrophage polarization. In addition to reprogram TAM, pexidartinib also changed the composition of tumor-invasive T cells. After pexidartinib treatment, the total number of T cells, CD8+ T cells and Treg cells were all decreased, the ratio of CD8+T/Treg increased significantly. According to the analysis of cytokines and chemokines during the treatment of pexidartinib, CCL22, as a chemokine for Treg recruitment, significantly decreased after the treatment of pexidartinib. Base on the above observation, the combination of pexidartinib and PD-1 antibody were used in the treatment of lung adenocarcinoma subcutaneous tumor model, the combination therapy has significantly improved the efficacy of tumor treatment compared with the monotherapy. Meanwhile, compared with pexidartinib monotherapy, the combination treatment further switches the polarization status of tumor-associated macrophages. In summary, our results showed that the combination of pexidartinib and PD-1 antibody showed a synergy and significantly improved the anti-tumor efficacy, through pexidartinib increasing CD8T/Treg ratio by reducing TAM-derived CCL22.
    Keywords:  CCL22; PD-1; lung adenocarcinoma; pexidartinib; treg; tumor associated macrophage
    DOI:  https://doi.org/10.3389/fphar.2023.1092767
  55. Cancer Cell. 2023 Mar 10. pii: S1535-6108(23)00048-X. [Epub ahead of print]
    A progressive T cell exhaustion program mapped across tissues in patients with lung cancer on immune checkpoint blockade.
    Carolina Mangana, Barbara B Maier.
      Immune checkpoint blockade has reached the standard of care for patients with lung cancer. However, its mode of action in patients is still incompletely understood. In this issue, Pai et al. present a temporally and spatially resolved differentiation map of tumor-directed T cells in patients with lung cancer on PD-1 blockade.
    DOI:  https://doi.org/10.1016/j.ccell.2023.02.020
  56. Cancer Res. 2023 Mar 27. pii: CAN-22-3864. [Epub ahead of print]
    Terminally exhausted CD8+ T cells resistant to PD-1 blockade promote generation and maintenance of aggressive cancer stem cells.
    Mohona Chakravarti, Sukanya Dhar, Saurav Bera, Abhipsa Sinha, Kamalika Roy, Anirban Sarkar, Shayani Dasgupta, Avishek Bhuniya, Akata Saha, Juhina Das, Saptak Banerjee, Manisha Vernekar, Chiranjib Pal, Neyaz Alam, Dipak Datta, Rathindranath Baral, Anamika Bose.
      Heterogeneity within the tumor infiltrating lymphocyte (TIL) population limits immunotherapeutic efficacy against cancer. Between two subpopulations of exhausted CD8+ TILs (progenitor-exhausted, TPEX; terminally-exhausted, TTEX), TTEX cells remain unresponsive to anti-PD1 therapy. Deciphering whether and how PD1-resistant TTEX cells engage in tumor promotion could improve the response to immunotherapy. Here, we report that TTEX cells actively participate in tumor progression by modulating cancer stem cells (CSC). TTEX cells strongly correlated with elevated CSC frequency in poorly immune-infiltrated (CD8+ TIL low) advanced human breast and ovarian carcinomas. TTEX directly upregulated CSC frequency in vitro, which was not affected by anti-PD1 treatment. The TTEX-influenced CSCs were highly clonogenic and exhibited a multi-drug resistant phenotype, overexpressing drug efflux pumps like ABCC1 and ABCB1. These CSCs were highly invasive, displaying increased invadopodia development and elevated cofilin, CXCR4, and MMP7 expression. The invasive properties along with epithelial-mesenchymal plasticity of TTEX-educated CSCs increased metastasis in vivo. TTEX increased cell surface levels and activation of VEGFR2 in CSCs, and silencing or inhibition of VEGFR2 reversed the CSC-stimulatory effects of TTEX. LAMP3 and NRP1 on the surface of TTEX stimulated VEGFR2 in CSCs to promote aggressiveness. Cumulatively, these findings suggest that screening carcinoma patients for both CD8+ TIL and TTEX frequency prior to anti-PD1-therapy could improve patient outcomes. Additionally, targeting the LAMP3/NRP1-VEGFR2 axis could be a therapeutic strategy in advanced carcinoma patients with limited CD8+ T cell infiltration and high TTEX frequency.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3864
  57. bioRxiv. 2023 Mar 15. pii: 2023.03.14.532663. [Epub ahead of print]
    Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
    Paul Renauer, Jonathan J Park, Meizhu Bai, Arianny Acosta, Won-Ho Lee, Guang Han Lin, Yueqi Zhang, Xiaoyun Dai, Guangchuan Wang, Youssef Errami, Terence Wu, Paul Clark, Lupeng Ye, Quanjun Yang, Sidi Chen.
      Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA -OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA -OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.Synopsis: The authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo .
    DOI:  https://doi.org/10.1101/2023.03.14.532663
  58. bioRxiv. 2023 Mar 15. pii: 2023.03.14.532668. [Epub ahead of print]
    Multiplexed repression of immunosuppressive genes as combinatorial cancer immunotherapy.
    Feifei Zhang, Guangchuan Wang, Ryan Chow, Emily He, Medha Majety, Yueqi Zhang, Sidi Chen.
      A complex set of pathways maintain an immunosuppressive tumor microenvironment (TME). Current cancer immunotherapies primarily rely on monoclonal antibodies targeting immune checkpoints, blocking one target at a time. Here, we devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile cancer immunotherapy approach. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intratumoral AAV-mediated administration of MUCIG (AAV-MUCIG) elicits significant anti-tumor activity with several Cas13d gRNA compositions. A simplified off-the-shelf AAV-MUCIG with four gene combination (PGGC: Pdl1 , Galectin9 , Galectin3 and Cd47 ) has anti-tumor efficacy across different tumor types and shows abscopal effect against metastatic cancer. AAV-PGGC remodeled the TME by increasing CD8 + T cell infiltration and reducing myeloid-derived immunosuppressive cells (MDSCs). Combining AAV-PGGC with Anti-Gr1 antibody that targets MDSCs achieves synergistic effect against metastatic cancer, which reduces tumor burden and extends survival.
    DOI:  https://doi.org/10.1101/2023.03.14.532668
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