bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–06–04
twenty-six papers selected by
Peio Azcoaga, Biodonostia HRI
  1. [Research Progress and New Immunotherapy Strategies of Tumor Microenvironment Metabolism].
  2. Dynamic polarization of tumor-associated macrophages and their interaction with intratumoral T cells in an inflamed tumor microenvironment: from mechanistic insights to therapeutic opportunities.
  3. Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy.
  4. Neuro-immune interactions and immuno-oncology.
  5. Immunogenetic metabolomics reveals key enzymes that modulate CAR T-cell metabolism and function.
  6. Garcinone E suppresses breast cancer growth and metastasis by modulating tumor-associated macrophages polarization via STAT6 signaling.
  7. Targeting breast cancer stem cells directly to treat refractory breast cancer.
  8. Cholesterol atlas of tumor microenvironment provides route to improved CAR-T therapy.
  9. Mechanosensitive changes in the expression of genes in colorectal cancer-associated fibroblasts.
  10. [Latest Findings on the Function of Immune Metabolism in Tumor Immunity].
  11. Cancer Associated Fibroblasts: An Understudied but Critical Component of the Tumor Microenvironment in Urothelial Cancer.
  12. The role of circular RNA in tumor microenvironment and immunotherapy.
  13. Editorial: Local and traditional medicine in regulation of the cancer immune suppression microenvironment, Volume II.
  14. The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity.
  15. Current state-of-the-art on ganglioside-mediated immune modulation in the tumor microenvironment.
  16. Efficient complement-mediated clearance of immunosuppressed T cells by macrophages.
  17. Interferon regulatory factor 7 in inflammation, cancer and infection.
  18. The role of PD-1 signaling in health and immune-related diseases.
  19. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.
  20. Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice.
  21. The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy.
  22. Chronic antigen in solid tumors drives a distinct program of T cell residence.
  23. Research progress of interleukin-15 in cancer immunotherapy.
  24. Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
  25. Age-associated PDGF-C drives breast cancer metastatic relapse.
  26. Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells.
  1. Sichuan Da Xue Xue Bao Yi Xue Ban. 2023 May;54(3): 505-509
    [Research Progress and New Immunotherapy Strategies of Tumor Microenvironment Metabolism].
    Yi-Man Peng, Xiang-Meng Luo, Jing-Yao Chen.
      The tumor microenvironment (TME), the environment of tumorigenesis and tumor progression, incorporates multiple types of cells and non-cellular components. TME plays an important role in tumorigenesis and tumor progression. Due to the abnormal proliferation of tumors, the TME has a unique chemophysiology environment and complex metabolic patterns, which subsequently affects the role of immune cells. Understanding the metabolic patterns of TME can help us develop immunotherapy regimens that target TME. Microbial metabolism and lipid metabolism, the key metabolic processes of TME, have emerged as important foci of research. The metabolites released by the microbiome and the reprogramming of cellular lipid metabolism affect the subsistence of tumor and immune cells. In this review, we summarized the composition and metabolic characteristics of TME and discussed the latest research progress in microbial metabolism and lipid metabolism in TME. We also provided an update on relevant metabolic regulatory targets and immunotherapy strategies, stressing that identifying highly effective therapeutic targets, in spite of the apparent difficulty, is what future research should be focused on.
    Keywords:  Immunotherapy; Lipid metabolism; Microbial metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.12182/20230560502
  2. Front Immunol. 2023 ;14 1160340
    Dynamic polarization of tumor-associated macrophages and their interaction with intratumoral T cells in an inflamed tumor microenvironment: from mechanistic insights to therapeutic opportunities.
    Jiashu Han, Luochu Dong, Mengwei Wu, Fei Ma.
      Immunotherapy has brought a paradigm shift in the treatment of tumors in recent decades. However, a significant proportion of patients remain unresponsive, largely due to the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play crucial roles in shaping the TME by exhibiting dual identities as both mediators and responders of inflammation. TAMs closely interact with intratumoral T cells, regulating their infiltration, activation, expansion, effector function, and exhaustion through multiple secretory and surface factors. Nevertheless, the heterogeneous and plastic nature of TAMs renders the targeting of any of these factors alone inadequate and poses significant challenges for mechanistic studies and clinical translation of corresponding therapies. In this review, we present a comprehensive summary of the mechanisms by which TAMs dynamically polarize to influence intratumoral T cells, with a focus on their interaction with other TME cells and metabolic competition. For each mechanism, we also discuss relevant therapeutic opportunities, including non-specific and targeted approaches in combination with checkpoint inhibitors and cellular therapies. Our ultimate goal is to develop macrophage-centered therapies that can fine-tune tumor inflammation and empower immunotherapy.
    Keywords:  immunometabolic dysregulation; immunotherapy; inflammation; macrophage polarization; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1160340
  3. Front Immunol. 2023 ;14 1172681
    Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy.
    Shipra Das, Julien Valton, Philippe Duchateau, Laurent Poirot.
      Adoptive cell therapy based on chimeric antigen receptor (CAR)-engineered T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intra-tumor infiltration by T cells and T cell dysfunction due to a desmoplastic, immunosuppressive microenvironment are key barriers for CAR T-cell success against solid tumors. Cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma, evolving specifically within the tumor microenvironment (TME) in response to tumor cell cues. The CAF secretome is a significant contributor to the extracellular matrix and a plethora of cytokines and growth factors that induce immune suppression. Together they form a physical and chemical barrier which induces a T cell-excluding 'cold' TME. CAF depletion in stroma rich solid tumors can thus provide an opportunity to convert immune evasive tumors susceptible to tumor-antigen CAR T-cell cytotoxicity. Using our TALEN-based gene editing platform we engineered non-alloreactive, immune evasive CAR T-cells (termed UCAR T-cells) targeting the unique CAF marker Fibroblast Activation Protein, alpha (FAP). In an orthotopic mouse model of triple-negative breast cancer (TNBC) composed of patient derived-CAFs and tumor cells, we demonstrate the efficacy of our engineered FAP UCAR T-cells in CAF depletion, reduction of desmoplasia and successful tumor infiltration. Furthermore, while previously resistant, pre-treatment with FAP UCAR T-cells now sensitized these tumors to Mesothelin (Meso) UCAR T-cell infiltration and anti-tumor cytotoxicity. Combination therapy of FAP UCAR, Meso UCAR T cells and the checkpoint inhibitor anti-PD-1 significantly reduced tumor burden and prolonged mice survival. Our study thus proposes a novel treatment paradigm for successful CAR T-cell immunotherapy against stroma-rich solid tumors.
    Keywords:  CAR T-cells; TALEN gene editing; allogeneic; cancer-associated fibroblasts; checkpoint inhibition; immunotherapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1172681
  4. Trends Cancer. 2023 May 30. pii: S2405-8033(23)00085-7. [Epub ahead of print]
    Neuro-immune interactions and immuno-oncology.
    Narmina Khanmammadova, Shajedul Islam, Padmanee Sharma, Moran Amit.
      The nervous system is an important component of the tumor microenvironment (TME), driving tumorigenesis and tumor progression. Neuronal cues (e.g., neurotransmitters and neuropeptides) in the TME cause phenotypic changes in immune cells, such as increased exhaustion and inhibition of effector cells, which promote immune evasion and cancer progression. Two types of immune regulation by tumor-associated nerves are discussed in this review: regulation via neuronal stimuli (i.e., by neural transmission) and checkpoint-mediated neuronal immune regulation. The latter occurs via the expression of immune checkpoints on the membranes of intratumoral nerves and glial cells. Here, we summarize novel findings regarding the neuroimmune circuits in the tumor milieu, while emphasizing the potential targets of new and affordable anticancer therapeutic approaches.
    Keywords:  cancer; immunology; immunotherapy; neuroimmunology; neuroscience; oncology
    DOI:  https://doi.org/10.1016/j.trecan.2023.05.002
  5. Cancer Immunol Res. 2023 May 30. pii: CIR-22-0565. [Epub ahead of print]
    Immunogenetic metabolomics reveals key enzymes that modulate CAR T-cell 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 investigated whether it is possible 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). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric-antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunological analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific 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-cell therapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0565
  6. Phytother Res. 2023 May 31.
    Garcinone E suppresses breast cancer growth and metastasis by modulating tumor-associated macrophages polarization via STAT6 signaling.
    Xin Nie, Li Fu, Yanfen Cheng, Xiaoping Wu, Kongpeng Lv, Renkai Li, Yihan Wu, George Pak-Heng Leung, Chaomei Fu, Simon Ming-Yuen Lee, Sai-Wang Seto, Jinming Zhang, Jingjing Li.
      Cancer metastasis remains the most common cause of death in breast cancer patients. Tumor-associated macrophages (TAMs) are a novel therapeutic target for the treatment of metastatic breast cancer. Despite the good anti-cancer activity of garcinone E (GE), there are no reports on its therapeutic effects on breast cancer metastasis. The objective of this study was to examine the anti-cancer effects of GE on metastatic breast cancer. RAW 264.7 and THP-1 cells were polarized to M2 macrophages by IL-4/IL-13 in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were used to explore the effect of GE on breast cancer growth and metastasis in vivo. In vitro studies showed that GE dose-dependently suppressed IL-4 + IL-13-induced expression of CD206 in both RAW 264.7 cells and differentiated THP-1 macrophages. However, GE did not affect the LPS + IFN-γ-induced polarization to the M1-like macrophages in vitro. GE inhibited the expression of the M2 macrophage specific genes in RAW 264.7 cells, and simultaneously impaired M2 macrophage-induced breast cancer cell proliferation and migration, and angiogenesis. In animal studies, GE significantly suppressed tumor growth, angiogenesis, and lung metastasis in 4T1 tumor-bearing mice, without causing toxicity. In both tumor and lung tissues, the proportion of M2-like TAMs was significantly decreased while the proportion of M1-like TAMs was markedly increased by GE treatment. Mechanistically, GE inhibited phosphorylation of STAT6 in vitro and in vivo. Our results demonstrate for the first time that GE suppresses breast cancer growth and pulmonary metastasis by modulating M2-like macrophage polarization through the STAT6 signaling pathway.
    Keywords:  Garcinone E; STAT6 signaling; breast cancer metastasis; tumor-associated macrophages
    DOI:  https://doi.org/10.1002/ptr.7909
  7. Front Oncol. 2023 ;13 981247
    Targeting breast cancer stem cells directly to treat refractory breast cancer.
    Liping Pan, Juan Han, Ming Lin.
      For patients with refractory breast cancer (BC), integrative immunotherapies are emerging as a critical component of treatment. However, many patients remain unresponsive to treatment or relapse after a period. Different cells and mediators in the tumor microenvironment (TME) play important roles in the progression of BC, and cancer stem cells (CSCs) are deemed the main cause of relapse. Their characteristics depend on their interactions with their microenvironment as well as on the inducing factors and elements in this environment. Strategies to modulate the immune system in the TME of BC that are aimed at reversing the suppressive networks within it and eradicating residual CSCs are, thus, essential for improving the current therapeutic efficacy of BC. This review focuses on the development of immunoresistance in BCs and discusses the strategies that can modulate the immune system and target breast CSCs directly to treat BC including immunotherapy with immune checkpoint blockades.
    Keywords:  breast cancer; cancer stem cells; immunoresistance; immunotherapy; oncology
    DOI:  https://doi.org/10.3389/fonc.2023.981247
  8. Cancer Cell. 2023 May 22. pii: S1535-6108(23)00180-0. [Epub ahead of print]
    Cholesterol atlas of tumor microenvironment provides route to improved CAR-T therapy.
    Adriano B Chaves-Filho, Almut Schulze.
      Cholesterol is essential for the ability of cytotoxic T cells to eliminate cancer cells. In this issue of Cancer Cell, Yan et al. reveal how intra-tumoral cholesterol deficiency contributes to T cell exhaustion by inhibiting mTORC1 signaling. Moreover, they demonstrate that increasing cholesterol levels in chimeric antigen receptor (CAR)-T cells by blocking liver X receptor (LXR) leads to improved anti-tumor function.
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.013
  9. Sci Data. 2023 Jun 02. 10(1): 350
    Mechanosensitive changes in the expression of genes in colorectal cancer-associated fibroblasts.
    Bashar Emon, You Jin Song, M Saddam H Joy, Mounisha V Kovour, Kannanganattu V Prasanth, M Taher A Saif.
      Most solid tumors become stiff with progression of cancer. Cancer Associated Fibroblasts (CAFs), most abundant stromal cells in the tumor microenvironment (TME), are known to mediate such stiffening. While the biochemical crosstalk between CAFs and cancer cells have been widely investigated, it is not clear if and how CAFs in stiffer TME promote metastatic progression. To gather insights into the process, we controlled the mechanical stiffness of the substrates and collected gene expression data with human colorectal CAFs. We cultured human primary CAFs on 2D polyacrylamide hydrogels with increasing elastic modulus (E) of 1, 10 and 40 kPa, and performed genome-wide transcriptome analyses in these cells to identify expression levels of ~16000 genes. The high-quality RNAseq results can be an excellent data-source for bioinformatic analysis for identifying novel pathways and biomarkers in cancer development and metastatic progression. With thorough analysis and accurate interpretation, this data may help researchers understand the role of mechanical stiffness of the TME in CAF-cancer cell crosstalk.
    DOI:  https://doi.org/10.1038/s41597-023-02233-9
  10. Sichuan Da Xue Xue Bao Yi Xue Ban. 2023 May;54(3): 497-504
    [Latest Findings on the Function of Immune Metabolism in Tumor Immunity].
    Yang Yang, Dian Fan, Bo-Hao Zheng, Sheng-Tao Zhou.
      Metabolic reprogramming, an important hallmark of cancer, helps cancer achieve rapid proliferation. Metabolic changes in tumors regulate multiple metabolic pathways of immune cells, thereby suppressing antitumor immunity. Recent studies have been focused on in-depth investigation into the changes in the metabolism of glucose, amino acids, and lipids. Researchers have also conducted in-depth exploration of the interactive metabolic regulation of tumor cells and immune cells. Targeting various metabolic mechanisms while combining available anti-tumor therapies and enhancing the anti-tumor effects of immunotherapy by satisfying the metabolic demands of immune cells has offered new perspectives for therapies targeting the immune metabolism of tumors and enhancing anti-tumor immune responses. Studies on novel immune checkpoint molecules and cellular immunotherapies are also ongoing. Herein, we reviewed the latest findings on the mechanisms of immune metabolism underlying tumor immunosuppression and their application in immunotherapy. We also suggested some ideas for the future development of the regulation of immune metabolism.
    Keywords:  Immune metabolism; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.12182/20230560304
  11. Eur Urol Oncol. 2023 May 31. pii: S2588-9311(23)00088-3. [Epub ahead of print]
    Cancer Associated Fibroblasts: An Understudied but Critical Component of the Tumor Microenvironment in Urothelial Cancer.
    Sean Clark-Garvey, Jeffrey S Damrauer, Matthew I Milowsky.
      
    DOI:  https://doi.org/10.1016/j.euo.2023.05.005
  12. Int J Biol Macromol. 2023 May 30. pii: S0141-8130(23)01823-8. [Epub ahead of print] 124929
    The role of circular RNA in tumor microenvironment and immunotherapy.
    Yu He, Qiu Huang, Yue Ge, Xiao Liu, Yonghua Tong, Haojie Shang, Ding Xia, Ejun Peng, Jian Wu, Zhiqiang Chen, Kun Tang.
      Cancer immunotherapy has favorable efficacy in various types of tumors, and has become an important weapon in the treatment of tumors in recent years. Long noncoding RNAs and microRNAs have been identified to play important roles in regulating cancer immunotherapy. Circular RNAs (circRNAs) are involved in the pathological process of many diseases, especially cancer. Many functions of circRNAs have been extensively studied. However, the functions of circRNAs in the tumor microenvironment and cancer immunotherapy do not appear to be fully elucidated. Therefore, we review the roles of circRNAs in tumor microenvironment and cancer immunotherapy.
    Keywords:  Immunotherapy; Tumor microenvironment; cancer; circRNAs
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.124929
  13. Front Pharmacol. 2023 ;14 1192478
    Editorial: Local and traditional medicine in regulation of the cancer immune suppression microenvironment, Volume II.
    Shicui Hong, Neng Wang, Zhiyu Wang.
      
    Keywords:  cancer; immunotherapy; local and traditional medicine; omics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1192478
  14. Front Oncol. 2023 ;13 1170264
    The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity.
    Vincenzo Salemme, Giorgia Centonze, Lidia Avalle, Dora Natalini, Alessio Piccolantonio, Pietro Arina, Alessandro Morellato, Ugo Ala, Daniela Taverna, Emilia Turco, Paola Defilippi.
      Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, and this heterogeneity is a crucial determinant of malignant progression and response to treatments. In addition to genetic diversity and plasticity of cancer cells, the tumor microenvironment contributes to tumor heterogeneity shaping the physical and biological surroundings of the tumor. The activity of certain types of immune, endothelial or mesenchymal cells in the microenvironment can change the effectiveness of cancer therapies via a plethora of different mechanisms. Therefore, deciphering the interactions between the distinct cell types, their spatial organization and their specific contribution to tumor growth and drug sensitivity is still a major challenge. Dissecting intra-tumor heterogeneity is currently an urgent need to better define breast cancer biology and to develop therapeutic strategies targeting the microenvironment as helpful tools for combined and personalized treatment. In this review, we analyze the mechanisms by which the tumor microenvironment affects the characteristics of tumor heterogeneity that ultimately result in drug resistance, and we outline state of the art preclinical models and emerging technologies that will be instrumental in unraveling the impact of the tumor microenvironment on resistance to therapies.
    Keywords:  breast cancer; cancer heterogenicity; drug resistance; molecular mechanisms; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1170264
  15. Cancer Metastasis Rev. 2023 Jun 02.
    Current state-of-the-art on ganglioside-mediated immune modulation in the tumor microenvironment.
    Irene van der Haar Àvila, Britt Windhouwer, Sandra J van Vliet.
      Gangliosides are sialylated glycolipids, mainly present at the cell surface membrane, involved in a variety of cellular signaling events. During malignant transformation, the composition of these glycosphingolipids is altered, leading to structural and functional changes, which are often negatively correlated to patient survival. Cancer cells have the ability to shed gangliosides into the tumor microenvironment, where they have a strong impact on anti-tumor immunity and promote tumor progression. Since most ganglioside species show prominent immunosuppressive activities, they might be considered checkpoint molecules released to counteract ongoing immunosurveillance. In this review, we highlight the current state-of-the-art on the ganglioside-mediated immunomodulation, specified for the different immune cells and individual gangliosides. In addition, we address the dual role that certain gangliosides play in the tumor microenvironment. Even though some ganglioside species have been more extensively studied than others, they are proven to contribute to the defense mechanisms of the tumor and should be regarded as promising therapeutic targets for inclusion in future immunotherapy regimens.
    Keywords:  Gangliosides; Glycosylation; Shedding; Tumor immunity
    DOI:  https://doi.org/10.1007/s10555-023-10108-z
  16. Front Immunol. 2023 ;14 1183180
    Efficient complement-mediated clearance of immunosuppressed T cells by macrophages.
    Angela A F Gankema, Charita Furumaya, Sara Fernández-Hermira, Mark Hoogenboezem, Hanke L Matlung, Robin van Bruggen, Taco W Kuijpers.
      Cancer is one of the leading causes of death worldwide. Treatment outcome is largely dictated by the tumor type, disease stage, and treatment success rates, but also by the variation among patients in endogenous anti-tumor responses. Studies indicate that the presence of neutrophils in the tumor microenvironment is associated with a worse patient outcome due to their ability to suppress local anti-tumor T cell activity. Our previous studies investigated the mechanisms by which neutrophils suppress and damage T cells to become smaller in size (small T cells), debilitating their effector activities. Several studies indicate a role for tumor-associated macrophages in scavenging damaged or dead cells. We hypothesized that the observed lack of small T cells in the TME by confocal microscopy is due to immediate uptake by macrophages. In this study, we confirmed that indeed only the smaller, damaged T cells are taken up by macrophages, once serum-opsonized. Damaged T cells opsonized with complement factor C3 fragments were phagocytosed by macrophages, resulting in almost instantaneous and highly efficient uptake of these small T cells. Inhibition of the complement receptors CR1, CR3 and CR4 expressed by macrophages completely blocked phagocytosis. By contrast, actively proliferating T cells (large T cells) were neither impaired in neutrophil-MDSC activity nor opsonized for phagocytosis by macrophages. Rapid removal of damaged T cells suggests a role of complement and macrophages within the tumor microenvironment to clear suppressed T cells in cancer patients.
    Keywords:  MDSC activity; T cells; complement; iC3b; macrophages; neutrophils; phagocytosis; trogocytosis
    DOI:  https://doi.org/10.3389/fimmu.2023.1183180
  17. Front Immunol. 2023 ;14 1190841
    Interferon regulatory factor 7 in inflammation, cancer and infection.
    Furong Qing, Zhiping Liu.
      Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factors (IRFs) family, is located downstream of the pattern recognition receptors (PRRs)-mediated signaling pathway and is essential for the production of type I interferon (IFN-I). Activation of IRF7 inhibits various viral and bacterial infections and suppresses the growth and metastasis of some cancers, but it may also affect the tumor microenvironment and promote the development of other cancers. Here, we summarize recent advances in the role of IRF7 as a multifunctional transcription factor in inflammation, cancer and infection by regulating IFN-I production or IFN-I-independent signaling pathways.
    Keywords:  IRF7; cancer; infection; inflammation; interferon
    DOI:  https://doi.org/10.3389/fimmu.2023.1190841
  18. Front Immunol. 2023 ;14 1163633
    The role of PD-1 signaling in health and immune-related diseases.
    Ru-Yue Chen, Yun Zhu, Yun-Yan Shen, Qin-Ying Xu, Han-Yun Tang, Ning-Xun Cui, Lu Jiang, Xiao-Mei Dai, Wei-Qing Chen, Qiang Lin, Xiao-Zhong Li.
      Programmed cell death 1 receptor (PD-1) and its ligands constitute an inhibitory pathway to mediate the mechanism of immune tolerance and provide immune homeostasis. Significantly, the binding partners of PD-1 and its associated ligands are diverse, which facilitates immunosuppression in cooperation with other immune checkpoint proteins. Accumulating evidence has demonstrated the important immunosuppressive role of the PD-1 axis in the tumor microenvironment and in autoimmune diseases. In addition, PD-1 blockades have been approved to treat various cancers, including solid tumors and hematological malignancies. Here, we provide a comprehensive review of the PD-1 pathway, focusing on the structure and expression of PD-1, programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2); the diverse biological functions of PD-1 signaling in health and immune-related diseases (including tumor immunity, autoimmunity, infectious immunity, transplantation immunity, allergy and immune privilege); and immune-related adverse events related to PD-1 and PD-L1 inhibitors.
    Keywords:  autoimmune diseases; immune checkpoint proteins; immune tolerance; immunotherapy; programmed cell death 1 receptor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1163633
  19. Cancer Cell. 2023 May 23. pii: S1535-6108(23)00142-3. [Epub ahead of print]
    Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.
    Chengsong Yan, Lin Zheng, Shutan Jiang, Haochen Yang, Jun Guo, Lu-Yi Jiang, Tongzhou Li, Haosong Zhang, Yibing Bai, Yu Lou, Qi Zhang, Tingbo Liang, Wolfgang Schamel, Haopeng Wang, Weiwei Yang, Guangchuan Wang, Zheng-Jiang Zhu, Bao-Liang Song, Chenqi Xu.
      The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit T cell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.
    Keywords:  CAR-T cells; Intratumoral T cells; autophagy-mediated apoptosis; cholesterol deficiency; cholesterol normalization; oxysterols
    DOI:  https://doi.org/10.1016/j.ccell.2023.04.016
  20. Eur J Immunol. 2023 May 30. e2250160
    Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice.
    Juanjuan Ye, Futoshi Suizu, Keiko Yamakawa, Yuri Mukai, Motohiko Kato, Hiroyuki Yoneyama, Naohisa Yahagi, Yoko Matsuda.
      Limited intratumoral T-cell infiltration in pancreatic ductal adenocarcinoma (PDAC) is an obstacle to immunotherapy, yet the efficient approach to enhance tumor-infiltrating T cells is not fully established. Here, we show that tumor-specific knockdown of carbohydrate sulfotransferase 15 (CHST15), a tumor stromal proteoglycan-synthetic enzyme, suppresses tumor growth in a T-cell-dependent manner in a murine model of PDAC. Silencing of tumoral CHST15 unexpectedly expanded CD4+ and CD8+ T cells in tumor draining LN (TDLN), leading to accelerated accumulation of EdU+ proliferating CD4+ and CD8+ T cells and granzyme B+ CD8+ T cells in the tumor. RNA expression analysis indicated that tumoral CHST15 knockdown (KD) downregulated matrix remodeling-related genes, while upregulated anti-tumor T-cell activity-related genes in both tumor and TDLN. CHST15 KD significantly diminished intratumoral and TDLN Ly6C/G+ myeloid-derived suppressor cells prior to TDLN T-cell expansion, suggesting that tumoral CHST15 remotely regulated myeloid-derived suppressor cell mediated T-cell suppression in the TDLN. Our findings illustrate a novel immunotherapeutic potential of tumoral CHST15 blockage by reactivating T cells in immune suppressive TDLN of PDAC.
    Keywords:  Myeloid-derived suppressor cells (MDSCs); Pancreatic ductal adenocarcinoma (PDAC); T cell; Tumor draining lymph node (TDLN)
    DOI:  https://doi.org/10.1002/eji.202250160
  21. Front Pharmacol. 2023 ;14 1184794
    The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy.
    Jiaao Sun, Liyan Yu, Xueling Qu, Tao Huang.
      Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for over 3 decades and consist of three isotypes, including PPARα, γ, and β/δ, that were originally considered key metabolic regulators controlling energy homeostasis in the body. Cancer has become a leading cause of human mortality worldwide, and the role of peroxisome proliferator-activated receptors in cancer is increasingly being investigated, especially the deep molecular mechanisms and effective cancer therapies. Peroxisome proliferator-activated receptors are an important class of lipid sensors and are involved in the regulation of multiple metabolic pathways and cell fate. They can regulate cancer progression in different tissues by activating endogenous or synthetic compounds. This review emphasizes the significance and knowledge of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anti-cancer treatment by summarizing recent research on peroxisome proliferator-activated receptors. In general, peroxisome proliferator-activated receptors either promote or suppress cancer in different types of tumor microenvironments. The emergence of this difference depends on various factors, including peroxisome proliferator-activated receptor type, cancer type, and tumor stage. Simultaneously, the effect of anti-cancer therapy based on drug-targeted PPARs differs or even opposes among the three peroxisome proliferator-activated receptor homotypes and different cancer types. Therefore, the current status and challenges of the use of peroxisome proliferator-activated receptors agonists and antagonists in cancer treatment are further explored in this review.
    Keywords:  PPARs; anti-cancer therapy; cancer; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1184794
  22. Sci Immunol. 2023 Jun 08. 8(84): eadd5976
    Chronic antigen in solid tumors drives a distinct program of T cell residence.
    Noah V Gavil, Milcah C Scott, Eyob Weyu, Olivia C Smith, Stephen D O'Flanagan, Sathi Wijeyesinghe, Sahar Lotfi-Emran, Stephen L Shiao, Vaiva Vezys, David Masopust.
      Analyses of healthy tissue reveal signatures that identify resident memory CD8+ T cells (TRM), which survey tissues without recirculating. The density of TRM phenotype cells within solid tumors correlates favorably with prognosis, suggesting that intratumoral residents control cancer. However, residence has not been directly tested, and intratumoral TRM phenotype cells could instead reflect aspects of the microenvironment that correlate with prognosis. Using a breast cancer model in mice, we found that conventional TRM markers do not inform the tumor residence of either bystander or tumor-specific cells, which exhibit further distinct phenotypes in the tumor microenvironment and healthy mammary tissue. Rather, tumor-specific, stem progenitor CD8+ T cells migrate to tumors and become resident while acquiring select markers of exhaustion. These data indicate that tonic antigen stimulation and the tumor environment drive distinct programs of residence compared with healthy tissues and that tumor immunity is sustained by continued migration of tumor-specific stem cells.
    DOI:  https://doi.org/10.1126/sciimmunol.add5976
  23. Front Pharmacol. 2023 ;14 1184703
    Research progress of interleukin-15 in cancer immunotherapy.
    Menghan Cai, Xuan Huang, Xiting Huang, Dianwen Ju, Yi Zhun Zhu, Li Ye.
      Interleukin-15 (IL-15) is a cytokine that belongs to the interleukin-2 (IL-2) family and is essential for the development, proliferation, and activation of immune cells, including natural killer (NK) cells, T cells and B cells. Recent studies have revealed that interleukin-15 also plays a critical role in cancer immunotherapy. Interleukin-15 agonist molecules have shown that interleukin-15 agonists are effective in inhibiting tumor growth and preventing metastasis, and some are undergoing clinical trials. In this review, we will summarize the recent progress in interleukin-15 research over the past 5 years, highlighting its potential applications in cancer immunotherapy and the progress of interleukin-15 agonist development.
    Keywords:  cancer; cancer immunotherapy; cytokines; interleukin-15 agonist; recombinant fusion proteins
    DOI:  https://doi.org/10.3389/fphar.2023.1184703
  24. Cell Rep. 2023 May 30. pii: S2211-1247(23)00593-4. [Epub ahead of print]42(6): 112582
    Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
    Kelly Kersten, Ran You, Sophia Liang, Kevin M Tharp, Joshua Pollack, Valerie M Weaver, Matthew F Krummel, Mark B Headley.
      Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.
    Keywords:  CP: Cancer; CP: Metabolism; infinity flow; lung; macrophages; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2023.112582
  25. Nat Aging. 2023 May 30.
    Age-associated PDGF-C drives breast cancer metastatic relapse.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-023-00437-7
  26. iScience. 2023 Jun 16. 26(6): 106827
    Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells.
    Jianping He, Abigail M Abikoye, Brett P McLaughlin, Ryan S Middleton, Ryan Sheldon, Russell G Jones, Zachary T Schafer.
      Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. Although alterations in membrane lipid content are observed during ECM detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM detachment because of changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of ferritin sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy toward ECM-detached cells.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106827
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