bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–04–28
28 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Factors affecting heterogeneity in breast cancer microenvironment: A narrative mini review.
  2. Signaling by Type I Interferons in Immune Cells: Disease Consequences.
  3. [Advances in Research on Cell Metabolic Interactions in the Tumor Microenvironment].
  4. Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles.
  5. The Tumor Microenvironment: Signal Transduction.
  6. The role of alpha-fetoprotein in the tumor microenvironment of hepatocellular carcinoma.
  7. Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy.
  8. Editorial: Extracellular vesicles as means of the activation, metabolic change induction, and remodeling of the tumor microenvironment.
  9. Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis.
  10. The role of tumor-associated macrophages in hepatocellular carcinoma-from bench to bedside: A review.
  11. Editorial: Harnessing tumor microenvironment for gynecologic cancer therapy.
  12. Regulatory role of CD39 and CD73 in tumor immunity.
  13. The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.
  14. CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy.
  15. Spatial dissection of the immune landscape of solid tumors to advance precision medicine.
  16. Immunological Mechanisms behind Anti-PD-1/PD-L1 Immune Checkpoint Blockade: Intratumoral Reinvigoration or Systemic Induction?
  17. Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.
  18. IL1R2 blockade alleviates immunosuppression and potentiates anti-PD-1 efficacy in triple-negative breast cancer.
  19. Plasticity and resistance of cancer stem cells as a challenge for innovative anticancer therapies - do we know enough to overcome this?
  20. Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer.
  21. Progress of research on the relationship between efferocytosis and tumor.
  22. Fusobacterium nucleatum carcinogenesis and drug delivery interventions.
  23. Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights.
  24. Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment.
  25. MDSCs in bone metastasis: mechanisms and therapeutic potential1.
  26. Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.
  27. Role of Tumor-Associated Macrophages in Cervical Cancer: Integrating Classical Perspectives with Recent Technological Advances.
  28. Metabolic vulnerability of cancer stem cells and their niche.
  1. Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00012-1. [Epub ahead of print]385 211-226
    Factors affecting heterogeneity in breast cancer microenvironment: A narrative mini review.
    Anirban Ganguly, Sumit Mukherjee, Kaushiki Chatterjee, Sheila Spada.
      Breast cancer (BC) heterogeneity is a key trait of BC tumors with crucial implications on tumorigenesis, diagnosis, and therapeutic modalities. It is influenced by tumor intrinsic features and by the tumor microenvironment (TME) composition of different intra-tumoral regions, which in turn affect cancer progression within patients. In this mini review, we will highlight the mechanisms that generate cancer heterogeneity in BC and how they affect the responses to cancer therapies.
    Keywords:  CAR-T cells; Epigenetics; Immune cell distribution; Immune checkpoint blockade; Immunotherapy; Matrix remodeling; Solid tumor; Tumor heterogeneity
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.01.002
  2. Cancers (Basel). 2024 Apr 22. pii: 1600. [Epub ahead of print]16(8):
    Signaling by Type I Interferons in Immune Cells: Disease Consequences.
    Markella Zannikou, Eleanor N Fish, Leonidas C Platanias.
      This review addresses interferon (IFN) signaling in immune cells and the tumor microenvironment (TME) and examines how this affects cancer progression. The data reveal that IFNs exert dual roles in cancers, dependent on the TME, exhibiting both anti-tumor activity and promoting cancer progression. We discuss the abnormal IFN signaling induced by cancerous cells that alters immune responses to permit their survival and proliferation.
    Keywords:  B cells; NK cells; T cell; cancer; dendritic cell; immune cells; interferons; macrophage; neutrophils; signaling; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16081600
  3. Sichuan Da Xue Xue Bao Yi Xue Ban. 2024 Mar 20. 55(2): 482-489
    [Advances in Research on Cell Metabolic Interactions in the Tumor Microenvironment].
    Pengfei Wu, Zhi Yang, Qingyan Li, Denian Wang.
      Metabolic reprogramming plays a critical role in tumorigenesis and tumor progression. The metabolism and the proliferation of tumors are regulated by both intrinsic factors within the tumor and the availability of metabolites in the tumor microenvironment (TME). The metabolic niche within the TME is primarily orchestrated at 3 levels: 1) the regulation of tumor metabolism by factors intrinsic to the tumors, 2) the interaction between tumor cells and T cells, macrophages, and stromal cells, and 3) the metabolic heterogeneity of tumor cells within the tissue space. Herein, we provided a concise overview of the various metabolic regulatory modes observed in tumor cells. Additionally, we extensively analyzed the interaction between tumor cells and other cells within the TME, as well as the metabolic characteristics and functions of different types of cells. Ultimately, this review provides a theoretical basis and novel insights for the precision treatment of tumors.
    Keywords:  Glycolysis; Metabolic heterogeneity; Metabolic reprogramming; Metabolic therapy; Review; Tumor microenvironment
    DOI:  https://doi.org/10.12182/20240360606
  4. Cells. 2024 Apr 15. pii: 682. [Epub ahead of print]13(8):
    Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles.
    Artem Ten, Vadim Kumeiko, Vladislav Farniev, Huile Gao, Maxim Shevtsov.
      The tumor microenvironment (TME) plays an important role in the process of tumorigenesis, regulating the growth, metabolism, proliferation, and invasion of cancer cells, as well as contributing to tumor resistance to the conventional chemoradiotherapies. Several types of cells with relatively stable phenotypes have been identified within the TME, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), neutrophils, and natural killer (NK) cells, which have been shown to modulate cancer cell proliferation, metastasis, and interaction with the immune system, thus promoting tumor heterogeneity. Growing evidence suggests that tumor-cell-derived extracellular vesicles (EVs), via the transfer of various molecules (e.g., RNA, proteins, peptides, and lipids), play a pivotal role in the transformation of normal cells in the TME into their tumor-associated protumorigenic counterparts. This review article focuses on the functions of EVs in the modulation of the TME with a view to how exosomes contribute to the transformation of normal cells, as well as their importance for cancer diagnosis and therapy.
    Keywords:  cancer stem cell; cancer-associated endothelial cells; cancer-associated fibroblast; cancer-associated neutrophil; exosome; tumor microenvironment; tumor-associated macrophage
    DOI:  https://doi.org/10.3390/cells13080682
  5. Biomolecules. 2024 Apr 04. pii: 438. [Epub ahead of print]14(4):
    The Tumor Microenvironment: Signal Transduction.
    Xianhong Zhang, Haijun Ma, Yue Gao, Yabing Liang, Yitian Du, Shuailin Hao, Ting Ni.
      In the challenging tumor microenvironment (TME), tumors coexist with diverse stromal cell types. During tumor progression and metastasis, a reciprocal interaction occurs between cancer cells and their environment. These interactions involve ongoing and evolving paracrine and proximal signaling. Intrinsic signal transduction in tumors drives processes such as malignant transformation, epithelial-mesenchymal transition, immune evasion, and tumor cell metastasis. In addition, cancer cells embedded in the tumor microenvironment undergo metabolic reprogramming. Their metabolites, serving as signaling molecules, engage in metabolic communication with diverse matrix components. These metabolites act as direct regulators of carcinogenic pathways, thereby activating signaling cascades that contribute to cancer progression. Hence, gaining insights into the intrinsic signal transduction of tumors and the signaling communication between tumor cells and various matrix components within the tumor microenvironment may reveal novel therapeutic targets. In this review, we initially examine the development of the tumor microenvironment. Subsequently, we delineate the oncogenic signaling pathways within tumor cells and elucidate the reciprocal communication between these pathways and the tumor microenvironment. Finally, we give an overview of the effect of signal transduction within the tumor microenvironment on tumor metabolism and tumor immunity.
    Keywords:  signaling pathways; tumor immunity; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom14040438
  6. Front Oncol. 2024 ;14 1363695
    The role of alpha-fetoprotein in the tumor microenvironment of hepatocellular carcinoma.
    Yan Lu, Bo Lin, Mengsen Li.
      Hepatocellular carcinoma (HCC) is a prevalent malignant cancer worldwide, characterized by high morbidity and mortality rates. Alpha-fetoprotein (AFP) is a glycoprotein synthesized by the liver and yolk sac during fetal development. However, the serum levels of AFP exhibit a significant correlation with the onset and progression of HCC in adults. Extensive research has demonstrated that the tumor microenvironment (TME) plays a crucial role in the malignant transformation of HCC, and AFP is a key factor in the TME, promoting HCC development. The objective of this review was to analyze the existing knowledge regarding the role of AFP in the TME. Specifically, this review focused on the effect of AFP on various cells in the TME, tumor immune evasion, and clinical application of AFP in the diagnosis and treatment of HCC. These findings offer valuable insights into the clinical treatment of HCC.
    Keywords:  AFP; hepatocellular carcinoma; immune escape; immunotherapy; liver cancer stem cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2024.1363695
  7. Cell Rep. 2024 Apr 23. pii: S2211-1247(24)00469-8. [Epub ahead of print]43(5): 114141
    Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy.
    Andrea Ziblat, Brendan L Horton, Emily F Higgs, Ken Hatogai, Anna Martinez, Jason W Shapiro, Danny E C Kim, YuanYuan Zha, Randy F Sweis, Thomas F Gajewski.
      The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.
    Keywords:  4-1BB; 4-1BBL; Batf3-lineage dendritic cells; CD8(+) T cells; CP: Cancer; CP: Immunology; DC1s; PD-1/PD-L1 blockade; immunotherapy; immunotherapy efficacy; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114141
  8. Front Oncol. 2024 ;14 1407949
    Editorial: Extracellular vesicles as means of the activation, metabolic change induction, and remodeling of the tumor microenvironment.
    Michela Pozzobon, Alfredo Cappariello.
      
    Keywords:  cancer progression; clinical outlooks; extracellular vesicles; tumor microenvironment; tumor niche remodeling
    DOI:  https://doi.org/10.3389/fonc.2024.1407949
  9. Cell Death Discov. 2024 Apr 22. 10(1): 189
    Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis.
    Cong Chen, Jian Liu, Xia Lin, Aizhai Xiang, Qianwei Ye, Jufeng Guo, Tao Rui, Jian Xu, Shufang Hu.
      Cancer-associated fibroblasts (CAFs), the main stromal component of the tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms of regulated cell death (RCD) in adjacent tumor cells, thus involving cancer proliferation, therapy resistance, and immune exclusion. Here, we present a brief introduction to CAFs and basic knowledge of RCD, including apoptosis, autophagy, ferroptosis, and pyroptosis. In addition, we further summarize the different types of RCD in tumors that are mediated by CAFs, as well as the effects of these modes of RCD on CAFs. This review will deepen our understanding of the interactions between CAFs and RCD and might offer novel therapeutic avenues for future cancer treatments.
    DOI:  https://doi.org/10.1038/s41420-024-01958-9
  10. J Gastroenterol Hepatol. 2024 Apr 23.
    The role of tumor-associated macrophages in hepatocellular carcinoma-from bench to bedside: A review.
    Maciej Gryziak, Leszek Kraj, Rafał Stec.
      Hepatocellular carcinoma is one of the most common cancers worldwide. Despite progress in treatment, recurrence after radical treatment is common, and the prognosis remains poor for patients with advanced disease. Therefore, there is a need to identify prognostic and predictive factors for the response to therapy or more intensive surveillance or treatment. Because the tumor microenvironment plays a crucial role in the development of cancer and metastasis, it is a crucial need to understand processes that are involved in carcinogenesis. Within the microenvironment, several immune cells with different roles are present. One of the most important of these is tumor-associated macrophages. These cells may exert either antitumor or protumor roles. Several studies have suggested that tumor-associated macrophages can be used as prognostic markers. Furthermore, they may be involved in resistance to immunotherapy or systemic treatment. As they play an important role in cancer development, tumor-associated macrophages are also a good target for therapy. In this review, we briefly summarize recent progress on knowledge regarding the basic molecular characteristics, impact on prognosis and potential clinical implications of tumor-associated macrophages in hepatocellular carcinoma.
    DOI:  https://doi.org/10.1111/jgh.16564
  11. Front Immunol. 2024 ;15 1407128
    Editorial: Harnessing tumor microenvironment for gynecologic cancer therapy.
    Linying Zhou, Ming Yi.
      
    Keywords:  cancer immunotherapy; cervical cancer; gynecologic cancer; ovarian cancer; tumor microenvironment; uterine cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1407128
  12. Future Oncol. 2024 Apr 23.
    Regulatory role of CD39 and CD73 in tumor immunity.
    Nicole Kaplinsky, Kada Williams, Dean Watkins, Molly Adams, Laura Stanbery, John Nemunaitis.
      CD39 is the rate-limiting enzyme for the molecular signal cascade leading to the generation of ADP and adenosine monophosphate (AMP). In conjunction with CD73, CD39 converts adenosine triphosphate (ATP) to ADP and AMP, which leads to the accumulation of immunosuppressive adenosine in the tumor microenvironment. This review focuses on the role of CD39 and CD73 in immune response and malignant progression, including the expression of CD39 within the tumor microenvironment and its relationship to immune effector cells, and its role in antigen presentation. The role of CD39- and CD73-targeting therapeutics and cancer-directed clinical trials investigating CD39 modulation are also explored.
    Keywords:  CD39; CD73; ENTPD1; adenosine pathway; antigen; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.2217/fon-2023-0871
  13. Aging Cell. 2024 Apr 22. e14182
    The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.
    Wenqiang Zhang, Kexin Zhang, Junfeng Shi, Hongyan Qiu, Chengxia Kan, Yujie Ma, Ningning Hou, Fang Han, Xiaodong Sun.
      The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.
    Keywords:  cancer; senescence‐associated secretory phenotype; senescent; tumor microenvironment
    DOI:  https://doi.org/10.1111/acel.14182
  14. Front Immunol. 2024 ;15 1378739
    CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy.
    Jiawen Huang, Qian Yang, Wen Wang, Juan Huang.
      Chimeric antigen receptor (CAR) T cell therapy has transformed cancer immunotherapy. However, significant challenges limit its application beyond B cell-driven malignancies, including limited clinical efficacy, high toxicity, and complex autologous cell product manufacturing. Despite efforts to improve CAR T cell therapy outcomes, there is a growing interest in utilizing alternative immune cells to develop CAR cells. These immune cells offer several advantages, such as major histocompatibility complex (MHC)-independent function, tumor microenvironment (TME) modulation, and increased tissue infiltration capabilities. Currently, CAR products from various T cell subtypes, innate immune cells, hematopoietic progenitor cells, and even exosomes are being explored. These CAR products often show enhanced antitumor efficacy, diminished toxicity, and superior tumor penetration. With these benefits in mind, numerous clinical trials are underway to access the potential of these innovative CAR cells. This review aims to thoroughly examine the advantages, challenges, and existing insights on these new CAR products in cancer treatment.
    Keywords:  cancer treatment; cellular immunotherapy; chimeric antigen receptors; off-the-shelf products; toxicity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1378739
  15. Cancer Immunol Res. 2024 Apr 24.
    Spatial dissection of the immune landscape of solid tumors to advance precision medicine.
    Francesco Di Mauro, Giuseppina Arbore.
      Chemotherapeutics, radiation, targeted therapeutics and immunotherapeutics each demonstrate clinical benefits for a small subset of patients with solid malignancies. Immune cells infiltrating the tumor and the surrounding stroma play a critical role in shaping cancer progression and modulating therapy response. They do this by interacting with the other cellular and molecular components of the tumor microenvironment (TME). Spatial multi-OMICs technologies are rapidly evolving. Currently, such technologies allow high-throughput RNA and protein profiling and retain geographical information about the TME cellular architecture and the functional phenotype of tumor, immune and stromal cells. An in-depth spatial characterization of the heterogenous tumor immune landscape can improve not only the prognosis, but also the prediction of therapy response, directing cancer patients to more tailored and efficacious treatments. This review highlights recent advancements in spatial transcriptomics and proteomics profiling technologies and how these technologies are being applied for the dissection of the immune cell composition in solid malignancies in order to further both basic research in oncology and the implementation of precision treatments in the clinic.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0699
  16. Biomedicines. 2024 Mar 29. pii: 764. [Epub ahead of print]12(4):
    Immunological Mechanisms behind Anti-PD-1/PD-L1 Immune Checkpoint Blockade: Intratumoral Reinvigoration or Systemic Induction?
    Zhikun Guo, Jiangnan Yu, Zihan Chen, Shuxian Chen, Lei Wang.
      Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) has been widely used to treat many types of cancer. It is well established that PD-L1 expressing cancer cells could directly inhibit the cytotoxicity of PD-1+ T cells via PD-L1-PD-1 interaction. However, histological quantification of intratumoral PD-L1 expression provides limited predictive value and PD-L1 negative patients could still benefit from ICB treatment. Therefore, the current major clinical challenges are low objective response rate and unclear immunological mechanisms behind responding vs. non-responding patients. Here, we review recent studies highlighting the importance of longitudinal pre- and post-ICB treatment on patients with various types of solid tumor to elucidate the mechanisms behind ICB treatment. On one hand, ICB induces changes in the tumor microenvironment by reinvigorating intratumoral PD-1+ exhausted T cells ("releasing the brakes"). On the other hand, ICB can also affect systemic antitumor immunity in the tumor-draining lymph node to induce priming/activation of cancer specific T cells, which is evident by T cell clonal expansion/replacement in peripheral blood. These studies reveal that ICB treatment not only acts on the tumor microenvironment ("battlefield") but also acts on immune organs ("training camp") of patients with solid tumors. A deeper understanding of the immunological mechanisms behind ICB treatment will pave the way for further improvements in clinical response.
    Keywords:  cancer-immunity cycle; immune checkpoint blockade; lymph node; peripheral blood; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines12040764
  17. J Clin Invest. 2024 Apr 23. pii: e167826. [Epub ahead of print]
    Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.
    Ashley M Fuller, Hawley C Pruitt, Ying Liu, Valerie M Irizarry-Negron, Hehai Pan, Hoogeun Song, Ann DeVine, Rohan S Katti, Samir Devalaraja, Gabrielle E Ciotti, Michael V Gonzalez, Erik F Williams, Ileana Murazzi, Dimitris Ntekoumes, Nicolas Skuli, Hakon Hakonarson, Daniel J Zabransky, Jose G Trevino, Ashani Weeraratna, Kristy Weber, Malay Haldar, Joseph A Fraietta, Sharon Gerecht, T S Karin Eisinger-Mathason.
      CD8+ T cell dysfunction impedes anti-tumor immunity in solid cancers but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional co-activator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend upon oncogene-mediated ECM composition and remodeling.
    Keywords:  Cancer immunotherapy; Extracellular matrix; Oncology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI167826
  18. Cancer Res. 2024 Apr 24.
    IL1R2 blockade alleviates immunosuppression and potentiates anti-PD-1 efficacy in triple-negative breast cancer.
    Jie Xia, Lixing Zhang, Xilei Peng, Juchuanli Tu, Siqin Li, Xueyan He, Fengkai Li, Jiankun Qiang, Haonan Dong, Qiaodan Deng, Cuicui Liu, Jiahui Xu, Rui Zhang, Quentin Liu, Guohong Hu, Chong Liu, Yi-Zhou Jiang, Zhi-Ming Shao, Ceshi Chen, Suling Liu.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Interleukin-1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. Here, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAMs) to inhibit BTIC self-renewal and CD8+ T cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1β increased PD-L1 expression by interacting with the transcription factor yin yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PD-L1. Combined treatment with an IL1R2-neutralizing antibody and anti-PD-1 led to enhanced anti-tumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3429
  19. EXCLI J. 2024 ;23 335-355
    Plasticity and resistance of cancer stem cells as a challenge for innovative anticancer therapies - do we know enough to overcome this?
    Agnieszka Knopik-Skrocka, Alicja Sempowicz, Oliwia Piwocka.
      According to the CSC hypothesis, cancer stem cells are pivotal in initiating, developing, and causing cancer recurrence. Since the identification of CSCs in leukemia, breast cancer, glioblastoma, and colorectal cancer in the 1990s, researchers have actively investigated the origin and biology of CSCs. However, the CSC hypothesis and the role of these cells in tumor development model is still in debate. These cells exhibit distinct surface markers, are capable of self-renewal, demonstrate unrestricted proliferation, and display metabolic adaptation. CSC phenotypic plasticity and the capacity to EMT is strictly connected to the stemness state. CSCs show high resistance to chemotherapy, radiotherapy, and immunotherapy. The plasticity of CSCs is significantly influenced by tumor microenvironment factors, such as hypoxia. Targeting the genetic and epigenetic changes of cancer cells, together with interactions with the tumor microenvironment, presents promising avenues for therapeutic strategies. See also the Graphical abstract(Fig. 1).
    Keywords:  cancer stem cells; hypoxia; immunosuppression; plasticity; resistance; therapies; tumor heterogeneity
    DOI:  https://doi.org/10.17179/excli2024-6972
  20. Breast Cancer Res Treat. 2024 Apr 20.
    Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer.
    Robert Hsu, Batul Al-Zubeidy, Daniel Flores, Ari Nazarian, Aaron Baugh, Edgar Gonzalez, Sofi Castanon, Joanne Xiu, Irene Kang, Darcy Spicer, Heinz Josef Lenz, Lily Dara, Foluso O Ademuyiwa, W Michael Korn, Sheeba Irshad, Isaac S Chan, Evanthia T Roussos Torres.
       PURPOSE: Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease.
    METHODS: 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter.
    RESULTS: Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1+ expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4+, CD8+, and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells.
    CONCLUSIONS: LvMs are less likely to express PD-L1+ tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.
    Keywords:  Liver metastasis; Metastatic breast cancer; Tumor immune infiltration; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10549-024-07295-w
  21. Front Oncol. 2024 ;14 1361327
    Progress of research on the relationship between efferocytosis and tumor.
    Xuexin Yao, Ling Zhang, Siyi Sun, Aishuang Fu, Yanlei Ge.
      Tumors are genetic changes that develop in an organism as a result of many internal and external causes. They affect the biological behavior of cells, cause them to grow independently, and give rise to new, perpetually proliferating organisms. Recent research has supported the critical function of tumor-associated macrophages in the development, progression, and metastasis of tumors through efferocytosis. Yet, there is still much to learn about the mechanisms behind their contribution to tumor pathological processes. As a result, it's critical to actively investigate how cytosolic processes contribute to the growth of tumors and to create novel therapeutic approaches.
    Keywords:  efferocytosis; macrophages; tumor; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fonc.2024.1361327
  22. Adv Drug Deliv Rev. 2024 Apr 19. pii: S0169-409X(24)00141-8. [Epub ahead of print] 115319
    Fusobacterium nucleatum carcinogenesis and drug delivery interventions.
    Zhenzhen Chen, Leaf Huang.
      The microbiome has emerged as a significant biomarker and modulator in cancer development and treatment response. Recent research highlights the notable role of Fusobacterium nucleatum (F. nucleatum) in various tumor types, including breast, colorectal, esophageal, gastric, pancreatic, and lung cancers. Accumulating evidence suggests that the local microbial community forms an integral component of the tumor microenvironment, with bacterial communities within tumors displaying specificity to tumor types. Mechanistic investigations indicate that tumor-associated microbiota can directly influence tumor initiation, progression, and responses to chemotherapy or immunotherapy. This article presents a comprehensive review of microbial communities especially F. nucleatum in tumor tissue, exploring their roles and underlying mechanisms in tumor development, treatment, and prevention. When the tumor-associated F. nucleatum is killed, the host immune response is activated to recognize tumor cells. Bacteria epitopes restricted by the host antigens, can be identified for future anti-bacteria/tumor vaccine development.
    Keywords:  Cancer immunotherapy; Fusobacterium nucleatum; Immune system; Tumor-associated microbiota
    DOI:  https://doi.org/10.1016/j.addr.2024.115319
  23. Front Oncol. 2024 ;14 1358750
    Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights.
    Li Yi, Yihan Gai, Zhuo Chen, Kecan Tian, Pengfei Liu, Hongrui Liang, Xinyu Xu, Qiuyi Peng, Xiaoqing Luo.
      The tumor microenvironment is a complex ecosystem where various cellular and molecular interactions shape the course of cancer progression. Macrophage colony-stimulating factor (M-CSF) plays a pivotal role in this context. This study delves into the biological properties and functions of M-CSF in regulating tumor-associated macrophages (TAMs) and its role in modulating host immune responses. Through the specific binding to its receptor colony-stimulating factor 1 receptor (CSF-1R), M-CSF orchestrates a cascade of downstream signaling pathways to modulate macrophage activation, polarization, and proliferation. Furthermore, M-CSF extends its influence to other immune cell populations, including dendritic cells. Notably, the heightened expression of M-CSF within the tumor microenvironment is often associated with dismal patient prognoses. Therefore, a comprehensive investigation into the roles of M-CSF in tumor growth advances our comprehension of tumor development mechanisms and unveils promising novel strategies and approaches for cancer treatment.
    Keywords:  CSF-1R; cancer therapy; dendritic cells; immune modulation; macrophage colony-stimulating factor; tumor progression
    DOI:  https://doi.org/10.3389/fonc.2024.1358750
  24. Adv Healthc Mater. 2024 Apr 24. e2400219
    Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment.
    Nan Jia, Qi Wang, Wenpan Li, Dawei Chen, Haiyang Hu.
      The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all in one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all in one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved anti-fibrotic drug pirfenidone (PFD/TAFsomes) and anti-tumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAF activity, reshape the TME, and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all in one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC. This article is protected by copyright. All rights reserved.
    Keywords:  Chemo‐immunity treatment; Membrane fusion liposomes; Targeted drug delivery; Tumor microenvironment
    DOI:  https://doi.org/10.1002/adhm.202400219
  25. Cancer Lett. 2024 Apr 20. pii: S0304-3835(24)00299-4. [Epub ahead of print] 216906
    MDSCs in bone metastasis: mechanisms and therapeutic potential1.
    Zhi Li, Qi Xia, Yujie He, Lei Li, Peihao Yin.
      Bone metastasis (BM) is a frequent complication associated with advanced cancer that significantly increases patient mortality. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in BM progression by promoting angiogenesis, inhibiting immune responses, and inducing osteoclastogenesis. MDSCs induce immunosuppression through diverse mechanisms, including the generation of reactive oxygen species, nitric oxide, and immunosuppressive cytokines. Within the bone metastasis niche (BMN), MDSCs engage in intricate interactions with tumor, stromal, and bone cells, thereby establishing a complex regulatory network. The biological activities and functions of MDSCs are regulated by the microenvironment within BMN. Conversely, MDSCs actively contribute to microenvironmental regulation, thereby promoting BM development. A comprehensive understanding of the indispensable role played by MDSCs in BM is imperative for the development of novel therapeutic strategies. This review highlights the involvement of MDSCs in BM development, their regulatory mechanisms, and their potential as viable therapeutic targets.
    Keywords:  bone metastasis; myeloid-derived suppressor cells (MDSCs); traditional Chinese medicine; tumor microenvironment; tumor vaccine
    DOI:  https://doi.org/10.1016/j.canlet.2024.216906
  26. Cancers (Basel). 2024 Apr 11. pii: 1470. [Epub ahead of print]16(8):
    Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.
    Olamide T Olaoba, Ming Yang, Temitope I Adelusi, Tessa Maidens, Eric T Kimchi, Kevin F Staveley-O'Carroll, Guangfu Li.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.
    Keywords:  PDAC; desmoplasia; immunotherapy; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16081470
  27. Life (Basel). 2024 Mar 27. pii: 443. [Epub ahead of print]14(4):
    Role of Tumor-Associated Macrophages in Cervical Cancer: Integrating Classical Perspectives with Recent Technological Advances.
    Yeseul Choi, Donghyeon Lee, Na Young Kim, Incheol Seo, Nora Jee-Young Park, Gun Oh Chong.
      Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment, influencing cancer progression and contributing to poor prognosis. However, in cervical cancer (CC), their significance and involvement are relatively less studied than in other gynecological cancers such as ovarian and endometrial cancer. This review aims to provide an overview of TAMs, covering their origins and phenotypes and their impact on CC progression, along with major TAM-targeted therapeutic approaches. Furthermore, we advocate for the integration of cutting-edge research methodologies, such as single-cell RNA sequencing and spatial RNA sequencing, to enable in-depth and comprehensive investigations into TAMs in CC, which would be beneficial in leading to more personalized and effective immunotherapy strategies for patients with CC.
    Keywords:  M1-like phenotype; M2-like phenotype; angiogenesis; cervical cancer; metastasis; multi-omics; single-cell transcriptomics; spatial transcriptomics; tumor-associated macrophage
    DOI:  https://doi.org/10.3390/life14040443
  28. Front Pharmacol. 2024 ;15 1375993
    Metabolic vulnerability of cancer stem cells and their niche.
    Laura Marrone, Simona Romano, Chiara Malasomma, Valeria Di Giacomo, Andrea Cerullo, Rosetta Abate, Marialuisa Alessandra Vecchione, Deborah Fratantonio, Maria Fiammetta Romano.
      Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.
    Keywords:  anti-mitochondrial drugs in clinical trials; cancer stem cells; oxidative metabolism; tumor associated macrophages; tumor dormancy
    DOI:  https://doi.org/10.3389/fphar.2024.1375993
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