bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–05–21
twenty-six papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Cancer-Associated Fibroblasts and Extracellular Matrix: Therapeutical Strategies for Modulating the Cholangiocarcinoma Microenvironment.
  2. Regulatory T Cells Impact the State of Key Tumor Microenvironment Cells.
  3. Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.
  4. Role of the Tumor Microenvironment and the Influence of Epigenetics on the Tumor Microenvironment in Oral Carcinogenesis: Potential Implications.
  5. Editorial: Tumor microenvironment in bladder cancer.
  6. Significance of Cancer-Associated Fibroblasts in the Interactions of Cancer Cells with the Tumor Microenvironment of Heterogeneous Tumor Tissue.
  7. Increased OIT3 in macrophage promotes PD-L1 expression and hepatocellular carcinogenesis via NF-κB signaling.
  8. Role of neutrophils on cancer cells and other immune cells in the tumor microenvironment.
  9. Perivascular tumor-associated macrophages and their role in cancer progression.
  10. Tumor immune microenvironment (TIME) to enhance antitumor immunity.
  11. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
  12. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer.
  13. From Interaction to Intervention: How Mesenchymal Stem Cells Affect and Target Triple-Negative Breast Cancer.
  14. Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.
  15. The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy.
  16. TGFβ and the Tumor Microenvironment in Colorectal Cancer.
  17. The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma.
  18. Reciprocal Regulation of Cancer-Associated Fibroblasts and Tumor Microenvironment in Gastrointestinal Cancer: Implications for Cancer Dormancy.
  19. Impact of the Cancer Cell Secretome in Driving Breast Cancer Progression.
  20. The current advances and future directions of PD-1/PD-L1 blockade in head and neck squamous cell carcinoma (HNSCC) in the era of immunotherapy.
  21. Immunobiology of Cholangiocarcinoma.
  22. 5-FU mediated depletion of myeloid suppressor cells enhances T-cell infiltration and anti-tumor response in immunotherapy-resistant lung tumor.
  23. Lipid metabolism in tumor immunology and immunotherapy.
  24. Breast Cancer Immunity: It is TIME for the Next Chapter.
  25. Investigating Chemokine-Matrix Networks in Breast Cancer: Tenascin-C Sets the Tone for CCL2.
  26. Antibody-based cancer immunotherapy by targeting regulatory T cells.
  1. Curr Oncol. 2023 04 14. 30(4): 4185-4196
    Cancer-Associated Fibroblasts and Extracellular Matrix: Therapeutical Strategies for Modulating the Cholangiocarcinoma Microenvironment.
    Mirko Minini, Laura Fouassier.
      During the last decade, immunotherapy has radically changed perspectives on anti-tumor treatments. However, solid tumor treatment by immunotherapy has not met expectations. Indeed, poor clinical response to treatment has highlighted the need to understand and avoid immunotherapy resistance. Cholangiocarcinoma (CCA) is the second cause of hepatic cancer-related deaths because of drug inefficacy and chemo-resistance in a majority of patients. Thus, intense research is ongoing to better understand the mechanisms involved in the chemo-resistance processes. The tumor microenvironment (TME) may be involved in tumor therapy resistance by limiting drug access. Indeed, cells such as cancer-associated fibroblasts (CAFs) alter TME by producing in excess an aberrant extracellular matrix (ECM). Interestingly, CAFs are the dominant stromal component in CCA that secrete large amounts of stiff ECM. Stiff ECM could contribute to immune exclusion by limiting anti-tumor T-cells drop-in. Herein, we summarize features, functions, and interactions among CAFs, tumor-associated ECM, and immune cells in TME. Moreover, we discuss the strategies targeting CAFs and the remodeling of the ECM to improve immunotherapy and drug therapies.
    Keywords:  cancer-associated fibroblasts; extracellular matrix; immune-exclusion; tumor microenvironment
    DOI:  https://doi.org/10.3390/curroncol30040319
  2. Cancer Discov. 2023 May 19. OF1
    Regulatory T Cells Impact the State of Key Tumor Microenvironment Cells.
      Regulatory T cells affect the transcriptional programs of key accessory cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-073
  3. Cancer Lett. 2023 May 10. pii: S0304-3835(23)00174-X. [Epub ahead of print]564 216223
    Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.
    Rilan Bai, Jiuwei Cui.
      Cancer cells adapt to increasing energy and biosynthetic demands by reprogramming their metabolic pathways. Mitochondria are important organelles for the metabolic reprogramming of tumor cells. In addition to supplying energy, they play crucial roles in the survival, immune evasion, tumor progression, and treatment resistance of the hypoxic tumor microenvironment (TME) in cancer cells. With the development of the life sciences, scientists have gained an in-depth understanding of immunity, metabolism, and cancer, and numerous studies have emphasized that mitochondria are essential for tumor immune escape and the regulation of immune cell metabolism and activation. Moreover, recent evidence suggests that targeting the mitochondria-related pathway with anticancer drugs can initiate the killing of cancer cells by increasing the ability of cancer cells to be recognized by immune cells, tumor antigen presentation ability, and the anti-tumor function of immune cells. This review discusses the effects of mitochondrial morphology and function on the phenotype and function of immune cells under normal and TME conditions, the effects of mitochondrial changes in tumors and microenvironments on tumor immune escape and immune cell function, and finally focuses on the recent research progress and future challenges of novel anti-tumor immunotherapy strategies targeting mitochondria.
    Keywords:  Immune regulation; Immunotherapy; Mitochondria; Neoplasm; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216223
  4. Crit Rev Oncog. 2022 ;27(4): 47-64
    Role of the Tumor Microenvironment and the Influence of Epigenetics on the Tumor Microenvironment in Oral Carcinogenesis: Potential Implications.
    Sagar Dholariya, Ragini D Singh, Madhuri Radadiya, Deepak Parchwani, Gaurav Sharma, Rashid Mir.
      Oral cancer has become a significant problem throughout the world, particularly in countries that are still developing. Recent literature supports the contribution of components of the tumor microenvironment (TME) and the effect of epigenetic changes happening in the cells of the TME on oral cancer development and progression. In this review, we comprehensively examine the significance of TME in the development of OC along with the current understanding of the epigenetic modifications that regulate the TME and their cohesive impact on tumor traits and their potential as therapeutic targets.
    DOI:  https://doi.org/10.1615/CritRevOncog.2022047088
  5. Front Oncol. 2023 ;13 1208196
    Editorial: Tumor microenvironment in bladder cancer.
    Sergei Kusmartsev, Ja Hyeon Ku, Fabio Grizzi.
      
    Keywords:  bladder cancer; cancer immunotherapy; cancer inflammation; tumor heterogeneity; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2023.1208196
  6. Cancers (Basel). 2023 Apr 28. pii: 2536. [Epub ahead of print]15(9):
    Significance of Cancer-Associated Fibroblasts in the Interactions of Cancer Cells with the Tumor Microenvironment of Heterogeneous Tumor Tissue.
    Yoshimi Arima, Satoko Matsueda, Hideyuki Saya.
      The tumor microenvironment (TME) plays a key role in cancer development and progression, as well as contributes to the therapeutic resistance and metastasis of cancer cells. The TME is heterogeneous and consists of multiple cell types, including cancer-associated fibroblasts (CAFs), endothelial cells, and immune cells, as well as various extracellular components. Recent studies have revealed cross talk between cancer cells and CAFs as well as between CAFs and other TME cells, including immune cells. Signaling by transforming growth factor-β, derived from CAFs, has recently been shown to induce remodeling of tumor tissue, including the promotion of angiogenesis and immune cell recruitment. Immunocompetent mouse cancer models that recapitulate interactions of cancer cells with the TME have provided insight into the TME network and support the development of new anticancer therapeutic strategies. Recent studies based on such models have revealed that the antitumor action of molecularly targeted agents is mediated in part by effects on the tumor immune environment. In this review, we focus on cancer cell-TME interactions in heterogeneous tumor tissue, and we provide an overview of the basis for anticancer therapeutic strategies that target the TME, including immunotherapy.
    Keywords:  cancer-associated fibroblast; desmoplastic stroma; immune suppression; immunocompetent mouse model; immunotherapy; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15092536
  7. Exp Cell Res. 2023 May 16. pii: S0014-4827(23)00198-2. [Epub ahead of print] 113651
    Increased OIT3 in macrophage promotes PD-L1 expression and hepatocellular carcinogenesis via NF-κB signaling.
    Jiaqi Wen, Shuai Yang, Guifang Yan, Juan Lei, Xudong Liu, Nan Zhang, Jiangang Zhang, Huan Deng, Lei Wu, Yongsheng Li.
      Oncoprotein-induced transcript 3 (OIT3) facilitates macrophage M2 polarization and hepatocellular carcinoma (HCC) progression, however, whether OIT3 regulates tumor immunity remains largely unknown. Here we found that OIT3 was upregulated in HCC-associated macrophages, which inhibited CD4+ and CD8+ T-cell infiltration in the tumor microenvironment (TME). Mechanistically, OIT3 increased the expression of PD-L1 on tumor-associated macrophages (TAMs) by activating NF-κB signaling, blockade of NF-κB reversed the immunosuppressive activity of TAMs and dampens HCC tumorigenesis. Our findings provide the molecular basis for OIT3 enhancing tumor immunosuppression and highlighted a potential therapeutic strategy for targeting the TAMs of HCC.
    Keywords:  NF-κB signaling; Oncoprotein-induced transcript 3; PD-L1; Tumor associated macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113651
  8. Biochim Biophys Acta Mol Cell Res. 2023 May 16. pii: S0167-4889(23)00065-4. [Epub ahead of print] 119493
    Role of neutrophils on cancer cells and other immune cells in the tumor microenvironment.
    Junpei Zhong, Siwen Zong, Jiayang Wang, Mingrui Feng, Jie Wang, Hongyan Zhang, Lixia Xiong.
      The notion that neutrophils only perform a specific set of single functions in the body has changed with the advancement of research methods. As the most abundant myeloid cells in human blood, neutrophils are currently emerging as important regulators of cancer. Given the duality of neutrophils, neutrophil-based tumor therapy has been clinically carried out in recent years and has made some progress. But due to the complexity of the tumor microenvironment, the therapeutic effect is still not satisfactory. Therefore, in this review, we discuss the direct interaction of neutrophils with the five most common cancer cells and other immune cells in the tumor microenvironment. Also, this review covered current limitations, potential future possibilities, and therapeutic approaches targeting neutrophil function in cancer therapy.
    Keywords:  Immune cells; Neutrophils; TAN; Therapy strategy; cancer cells; cancer development
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119493
  9. Essays Biochem. 2023 May 18. pii: EBC20220242. [Epub ahead of print]
    Perivascular tumor-associated macrophages and their role in cancer progression.
    Meriem Bahri, Joanne E Anstee, James W Opzoomer, James N Arnold.
      Perivascular (Pv) tumor-associated macrophages (TAMs) are a highly specialized stromal subset within the tumor microenvironment (TME) that are defined by their spatial proximity, within one cell thickness, to blood vasculature. PvTAMs have been demonstrated to support a variety of pro-tumoral functions including angiogenesis, metastasis, and modulating the immune and stromal landscape. Furthermore, PvTAMs can also limit the response of anti-cancer and anti-angiogenic therapies and support tumor recurrence post-treatment. However, their role may not exclusively be pro-tumoral as PvTAMs can also have immune-stimulatory capabilities. PvTAMs are derived from a monocyte progenitor that develop and localize to the Pv niche as part of a multistep process which relies on a series of signals from tumor, endothelial and Pv mesenchymal cell populations. These cellular communications and signals create a highly specialized TAM subset that can also form CCR5-dependent multicellular 'nest' structures in the Pv niche. This review considers our current understanding of the role of PvTAMs, their markers for identification, development, and function in cancer. The role of PvTAMs in supporting disease progression and modulating the outcome from anti-cancer therapies highlight these cells as a therapeutic target. However, their resistance to pan-TAM targeting therapies, such as those targeting the colony stimulating factor-1 (CSF1)-CSF1 receptor axis, prompts the need for more targeted therapeutic approaches to be considered for this subset. This review highlights potential therapeutic strategies to target and modulate PvTAM development and function in the TME.
    Keywords:  cancer; macrophages; metastasis; perivascular; polarization; tumor microenvironments
    DOI:  https://doi.org/10.1042/EBC20220242
  10. Eur J Med Res. 2023 May 13. 28(1): 169
    Tumor immune microenvironment (TIME) to enhance antitumor immunity.
    Sajin Rajbhandary, Hari Dhakal, Sudip Shrestha.
      The tumor microenvironment is a result of dynamic interaction between different cellular and non-cellular components. In its essence it is not a solo performer, but an ensemble of performers that includes cancer cells, fibroblasts, myo-fibroblasts, endothelial cells and immune cells. The short review highlights important immune infiltrates within the tumor microenvironment that shape cytotoxic t lymphocyte (CTL)-rich immune hot and CTL-deficient immune cold tumors and novel strategies that have potential role in enhancing our immune responses in both immune hot and immune cold tumors.
    Keywords:  Anti-tumor immunity; Immune cold tumors; Immune hot tumors; Tumor immune infiltrates; Tumor immune microenvironment; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40001-023-01125-3
  11. Cell Metab. 2023 May 05. pii: S1550-4131(23)00171-7. [Epub ahead of print]
    Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
    Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang.
      Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
    Keywords:  CD8(+) T cell activation; FH; ZAP70; anti-tumor immune response; fumarate; fumarate hydrolase; succination; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.017
  12. Front Immunol. 2023 ;14 1163585
    The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer.
    Lincoln N Strickland, Erika Y Faraoni, Wei Ruan, Xiaoyi Yuan, Holger K Eltzschig, Jennifer M Bailey-Lundberg.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γδ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells.
    Keywords:  Adenosine receptor 2B; CD8+ T cell response; hypoxia; immunotherapy; pancreatic adenocarcinoma
    DOI:  https://doi.org/10.3389/fimmu.2023.1163585
  13. Biomedicines. 2023 Apr 15. pii: 1182. [Epub ahead of print]11(4):
    From Interaction to Intervention: How Mesenchymal Stem Cells Affect and Target Triple-Negative Breast Cancer.
    Yong Wu, Hang Chee Erin Shum, Ke Wu, Jaydutt Vadgama.
      Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expressions, making targeted therapies ineffective. Mesenchymal stem cells (MSCs) have emerged as a promising approach for TNBC treatment by modulating the tumor microenvironment (TME) and interacting with cancer cells. This review aims to comprehensively overview the role of MSCs in TNBC treatment, including their mechanisms of action and application strategies. We analyze the interactions between MSC and TNBC cells, including the impact of MSCs on TNBC cell proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance, along with the signaling pathways and molecular mechanisms involved. We also explore the impact of MSCs on other components of the TME, such as immune and stromal cells, and the underlying mechanisms. The review discusses the application strategies of MSCs in TNBC treatment, including their use as cell or drug carriers and the advantages and limitations of different types and sources of MSCs in terms of safety and efficacy. Finally, we discuss the challenges and prospects of MSCs in TNBC treatment and propose potential solutions or improvement methods. Overall, this review provides valuable insights into the potential of MSCs as a novel therapeutic approach for TNBC treatment.
    Keywords:  mesenchymal stem cells; metastasis; proliferation; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines11041182
  14. Cell Commun Signal. 2023 May 19. 21(1): 116
    Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.
    Chuwen Jiang, Zhengting Jiang, Gengyu Sha, Daorong Wang, Dong Tang.
      Metastasis, the spread of a tumor or cancer from the primary site of the body to a secondary site, is a multi-step process in cancer progression, accounting for various obstacles in cancer treatment and most cancer-related deaths. Metabolic reprogramming refers to adaptive metabolic changes that occur in cancer cells in the tumor microenvironment (TME) to enhance their survival ability and metastatic potential. Stromal cell metabolism also changes to stimulate tumor proliferation and metastasis. Metabolic adaptations of tumor and non-tumor cells exist not only in the TME but also in the pre-metastatic niche (PMN), a remote TME conducive for tumor metastasis. As a novel mediator in cell-to-cell communication, small extracellular vesicles (sEVs), which have a diameter of 30-150 nm, reprogram metabolism in stromal and cancer cells within the TME by transferring bioactive substances including proteins, mRNAs and miRNAs (microRNAs). sEVs can be delivered from the primary TME to PMN, affecting PMN formation in stroma rewriting, angiogenesis, immunological suppression and matrix cell metabolism by mediating metabolic reprogramming. Herein, we review the functions of sEVs in cancer cells and the TME, how sEVs facilitate PMN establishment to trigger metastasis via metabolic reprogramming, and the prospective applications of sEVs in tumor diagnosis and treatment. Video Abstract.
    Keywords:  Metabolic reprogramming; Metastasis; PMN; Tumor microenvironment; sEVs
    DOI:  https://doi.org/10.1186/s12964-023-01136-x
  15. Biomolecules. 2023 Apr 12. pii: 670. [Epub ahead of print]13(4):
    The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy.
    Daria Vinokurova, Lionel Apetoh.
      PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy.
    Keywords:  TH9 cells; anti-PD-1; cancer immunotherapy; interleukin 9
    DOI:  https://doi.org/10.3390/biom13040670
  16. Cells. 2023 04 12. pii: 1139. [Epub ahead of print]12(8):
    TGFβ and the Tumor Microenvironment in Colorectal Cancer.
    Maximilian J Waldner, Markus F Neurath.
      Growing evidence supports an important role of the tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC). Resident cells such as fibroblasts or immune cells infiltrating into the TME maintain continuous crosstalk with cancer cells and thereby regulate CRC progression. One of the most important molecules involved is the immunoregulatory cytokine transforming growth factor-β (TGFβ). TGFβ is released by various cells in the TME, including macrophages and fibroblasts, and it modulates cancer cell growth, differentiation, and cell death. Mutations in components of the TGF pathway, including TGFβ receptor type 2 or SMAD4, are among the most frequently detected mutations in CRC and have been associated with the clinical course of disease. Within this review, we will discuss our current understanding about the role of TGFβ in the pathogenesis of CRC. This includes novel data on the molecular mechanisms of TGFβ signaling in TME, as well as possible strategies for CRC therapy targeting the TGFβ pathway, including potential combinations with immune checkpoint inhibitors.
    Keywords:  SMAD4; TGFβ; colorectal cancer; immune response; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells12081139
  17. Int J Mol Sci. 2023 Apr 27. pii: 7946. [Epub ahead of print]24(9):
    The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma.
    Cesar U Monjaras-Avila, Ana C Lorenzo-Leal, Ana C Luque-Badillo, Ninadh D'Costa, Claudia Chavez-Muñoz, Horacio Bach.
      Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One of the critical features of the ccRCC TIME is the presence of infiltrating immune cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. Among these cells, CD8+ T cells are particularly important in controlling tumor growth by recognizing and killing cancer cells. However, the TIME of ccRCC is also characterized by an immunosuppressive environment that hinders the function of immune cells. Several mechanisms contribute to the immunosuppressive nature of the ccRCC TIME. For instance, ccRCC cells produce cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which suppress immune cell activation and promote the differentiation of regulatory T cells (Tregs). Tregs, in turn, dampen the activity of effector T cells and promote tumor growth. In addition, ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function. In addition, other immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3), also contribute to the immunosuppressive milieu of the ccRCC TIME. Finally, the hypoxic and nutrient-poor microenvironment of ccRCC can stimulate the production of immunosuppressive metabolites, such as adenosine and kynurenine, which further impair the function of immune cells. Understanding the complex interplay between tumor cells and the immune system in the ccRCC TIME is crucial for developing effective immunotherapies to treat this disease.
    Keywords:  TIME; ccRCC; clear cell renal cell carcinoma; mccRCC; metastatic clear cell renal cell carcinoma; renal cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.3390/ijms24097946
  18. Cancers (Basel). 2023 Apr 27. pii: 2513. [Epub ahead of print]15(9):
    Reciprocal Regulation of Cancer-Associated Fibroblasts and Tumor Microenvironment in Gastrointestinal Cancer: Implications for Cancer Dormancy.
    Shih-Hsuan Cheng, Hsin-Ying Clair Chiou, Jiunn-Wei Wang, Ming-Hong Lin.
      Gastrointestinal (GI) cancers remain a major cause of cancer-related deaths worldwide. Despite the progress made in current treatments, patients with GI cancers still have high recurrence rates after initial treatment. Cancer dormancy, which involves the entry and escape of cancer cells from dormancy, is linked to treatment resistance, metastasis, and disease relapse. Recently, the role of the tumor microenvironment (TME) in disease progression and treatment has received increasing attention. The crosstalk between cancer-associated fibroblasts (CAF)-secreted cytokines/chemokines and other TME components, for example, extracellular matrix remodeling and immunomodulatory functions, play crucial roles in tumorigenesis. While there is limited direct evidence of a relationship between CAFs and cancer cell dormancy, this review explores the potential of CAF-secreted cytokines/chemokines to either promote cancer cell dormancy or awaken dormant cancer cells under different conditions, and the therapeutic strategies that may be applicable. By understanding the interactions between cytokines/chemokines released by CAFs and the TME, and their impact on the entry/escape of cancer dormancy, researchers may develop new strategies to reduce the risk of therapeutic relapse in patients with GI cancers.
    Keywords:  cancer-associated fibroblasts (CAFs); cytokines; dormancy; the tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers15092513
  19. Cancers (Basel). 2023 May 08. pii: 2653. [Epub ahead of print]15(9):
    Impact of the Cancer Cell Secretome in Driving Breast Cancer Progression.
    Syazalina Zahari, Saiful Effendi Syafruddin, M Aiman Mohtar.
      Breast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has uncovered a compelling link between breast cancer onset and the extracellular environment enveloping tumor cells. The complex network of proteins secreted by cancer cells and other cellular components within the tumor microenvironment has emerged as a critical player in driving the disease's metastatic properties. Specifically, the proteins released by the tumor cells termed the secretome, can significantly influence the progression and metastasis of breast cancer. The breast cancer cell secretome promotes tumorigenesis through its ability to modulate growth-associated signaling pathways, reshaping the tumor microenvironment, supporting pre-metastatic niche formation, and facilitating immunosurveillance evasion. Additionally, the secretome has been shown to play a crucial role in drug resistance development, making it an attractive target for cancer therapy. Understanding the intricate role of the cancer cell secretome in breast cancer progression will provide new insights into the underlying mechanisms of this disease and aid in the development of more innovative therapeutic interventions. Hence, this review provides a nuanced analysis of the impact of the cancer cell secretome on breast cancer progression, elucidates the complex reciprocal interaction with the components of the tumor microenvironment and highlights emerging therapeutic opportunities for targeting the constituents of the secretome.
    Keywords:  drug resistance; immune modulation; metastasis; precision oncology; secretome; therapeutic targets; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15092653
  20. Int Immunopharmacol. 2023 May 17. pii: S1567-5769(23)00652-5. [Epub ahead of print]120 110329
    The current advances and future directions of PD-1/PD-L1 blockade in head and neck squamous cell carcinoma (HNSCC) in the era of immunotherapy.
    Yunhao Chen, Xingchen Ding, Xinbin Bai, Zihan Zhou, Yu Liu, Xianbin Zhang, Jinming Yu, Man Hu.
      Immune checkpoint inhibitors (ICIs) have previously demonstrated their efficacy and safety in various solid tumors, and with the growing interest in the application of ICIs in head and neck squamous cell carcinoma (HNSCC), various data have been reported. Mechanistically, HNSCC cells express programmed death ligand 1 (PD-L1), which binds to its receptor programmed death 1 (PD-1). Immune escape plays a key role in disease initiation and progression. Studying the abnormal activation of related pathways of PD-1/PD-L1 will help to understand the way of immunotherapy and find the advantageous population of immunotherapy. How to reduce HNSCC-related mortality and morbidity in this process has promoted the search for new therapeutic strategies, especially in the era of immunotherapy. PD-1 inhibitors have demonstrated significant prolongation of survival in recurrent/metastatic (R/M) HNSCC with a favorable safety profile. It also holds great promise in locally advanced (LA) HNSCC, where numerous studies are underway. Although immunotherapy has made great progress in HNSCC research, there are still many challenges. Therefore, in the review, we conducted an in-depth study on the expression of PD-L1 and the regulatory, immunosuppressive mechanisms caused by PD-L1, especially in head and neck squamous cell carcinoma, which is different from other tumors. And further summarize the situation, challenges and development trends of PD-1 and PD-L1 blockade in clinical practice.
    Keywords:  Immunotherapy; LA HNSCC; PD-1/PD-L1 inhibitors; R/M HNSCC
    DOI:  https://doi.org/10.1016/j.intimp.2023.110329
  21. J Hepatol. 2023 May 16. pii: S0168-8278(23)00338-0. [Epub ahead of print]
    Immunobiology of Cholangiocarcinoma.
    Jennifer L Tomlinson, Juan W Valle, Sumera I Ilyas.
      Recent literature has significantly advanced our knowledge and understanding of the cholangiocarcinoma tumor immune microenvironment. Detailed characterization of the immune landscape has defined new patient subtypes. While not utilized in clinical practice yet, these novel classifications will help inform decisions regarding immunotherapeutic approaches. Suppressive immune cells, such as tumor-associated macrophages and myeloid derived suppressor cells, form a barrier that shields tumor cells from immune surveillance. The presence of this immunosuppressive barrier in combination with a variety of immune escape mechanisms employed by tumor cells lead to poor tumor immunogenicity. Broad strategies to re-equip the immune system include blockade of suppressive immune cell recruitment to priming cytotoxic effector cells against tumor antigens. While immunotherapeutic strategies are gaining traction in the treatment of cholangiocarcinoma, there is a long road of discovery ahead in order to make meaningful contributions to patient therapy and survival.
    Keywords:  Immunosuppressive myeloid cells; immune evasion; immunogenic; preclinical models
    DOI:  https://doi.org/10.1016/j.jhep.2023.05.010
  22. Int Immunopharmacol. 2023 May 16. pii: S1567-5769(23)00450-2. [Epub ahead of print]120 110129
    5-FU mediated depletion of myeloid suppressor cells enhances T-cell infiltration and anti-tumor response in immunotherapy-resistant lung tumor.
    Ambily Anna Mathew, Zahara T Zakkariya, Anusha Ashokan, Maneesh Manohar, Pavithran Keechilat, Shantikumar V Nair, Manzoor Koyakutty.
      Tumor microenvironment (TME) is a heterogeneous system consisting of both cellular and acellular components. The growth and progression of tumors rely greatly on the nature of TME, marking it as an important target in cancer immunotherapy. Lewis Lung Carcinoma (LLC) is an established murine lung cancer model representing immunologically 'cold' tumors characterized by very few infiltrated cytotoxic T-cells, high levels of Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs). Here, we report various strategies we applied to reverse the non-immunogenic character of this cold tumor by imparting: a) immunogenic cell death using Hypericin nanoparticle-based photodynamic therapy (PDT), b) repolarising TAM using a TLR7/8 agonist, resiquimod, c) immune checkpoint inhibition using anti-PD-L1 and d) depleting MDSCs using low-dose 5-fluorouracil (5-FU) chemotherapy. Interestingly, the nano-PDT, resiquimod or anti-PD-L1 treatment had no major impact on tumor growth, whereas low-dose 5-FU-mediated depletion of MDSCs showed significant anti-tumor effect, primarily caused by the increased infiltration of CD8+ cytotoxic T-cells (∼96%). Though we have tested combining PDT with resiquimod or 5-FU for any synergistic effect, low-dose 5-FU alone showed better response than combinations. In effect, we show that depletion of MDSCs using low-dose 5-FU was one of the best methods to augment infiltration of CD8+ cytotoxic T-cells into a cold tumor, which is resistant to conventional therapies including immune checkpoint inhibitors.
    Keywords:  Cold tumor; Lewis lung carcinoma; Myeloid-derived suppressor cells; T-cell infiltration; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2023.110129
  23. Front Oncol. 2023 ;13 1187279
    Lipid metabolism in tumor immunology and immunotherapy.
    Lisa K Duong, Halil Ibrahim Corbali, Thomas S Riad, Shonik Ganjoo, Selene Nanez, Tiffany Voss, Hampartsum Barsomium, James Welsh, Maria Angelica Cortez.
      Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer.
    Keywords:  cancer; immune cells; immunotherapy; lipid oxidation; lipids
    DOI:  https://doi.org/10.3389/fonc.2023.1187279
  24. Cold Spring Harb Perspect Med. 2023 May 15. pii: a041324. [Epub ahead of print]
    Breast Cancer Immunity: It is TIME for the Next Chapter.
    Daniela F Quail, Morag Park, Alana L Welm, H Atakan Ekiz.
      Our ability to interrogate the tumor immune microenvironment (TIME) at an ever-increasing granularity has uncovered critical determinants of disease progression. Not only do we now have a better understanding of the immune response in breast cancer, but it is becoming possible to leverage key mechanisms to effectively combat this disease. Almost every component of the immune system plays a role in enabling or inhibiting breast tumor growth. Building on early seminal work showing the involvement of T cells and macrophages in controlling breast cancer progression and metastasis, single-cell genomics and spatial proteomics approaches have recently expanded our view of the TIME. In this article, we provide a detailed description of the immune response against breast cancer and examine its heterogeneity in disease subtypes. We discuss preclinical models that enable dissecting the mechanisms responsible for tumor clearance or immune evasion and draw parallels and distinctions between human disease and murine counterparts. Last, as the cancer immunology field is moving toward the analysis of the TIME at the cellular and spatial levels, we highlight key studies that revealed previously unappreciated complexity in breast cancer using these technologies. Taken together, this article summarizes what is known in breast cancer immunology through the lens of translational research and identifies future directions to improve clinical outcomes.
    DOI:  https://doi.org/10.1101/cshperspect.a041324
  25. Int J Mol Sci. 2023 May 06. pii: 8365. [Epub ahead of print]24(9):
    Investigating Chemokine-Matrix Networks in Breast Cancer: Tenascin-C Sets the Tone for CCL2.
    Martha Gschwandtner, Anís N Gammage, Claire Deligne, Linda F M Mies, Alissa Domaingo, Devardarssen Murdamoothoo, Thomas Loustau, Anja Schwenzer, Rupert Derler, Raphael Carapito, Manuel Koch, Matthias Mörgelin, Gertraud Orend, Andreas J Kungl, Kim S Midwood.
      Bidirectional dialogue between cellular and non-cellular components of the tumor microenvironment (TME) drives cancer survival. In the extracellular space, combinations of matrix molecules and soluble mediators provide external cues that dictate the behavior of TME resident cells. Often studied in isolation, integrated cues from complex tissue microenvironments likely function more cohesively. Here, we study the interplay between the matrix molecule tenascin-C (TNC) and chemokine CCL2, both elevated in and associated with the progression of breast cancer and playing key roles in myeloid immune responses. We uncover a correlation between TNC/CCL2 tissue levels in HER2+ breast cancer and examine the physical and functional interactions of these molecules in a murine disease model with tunable TNC levels and in in vitro cellular and cell-free models. TNC supported sustained CCL2 synthesis, with chemokine binding to TNC via two distinct domains. TNC dominated the behavior of tumor-resident myeloid cells; CCL2 did not impact macrophage survival/activation whilst TNC facilitated an immune suppressive macrophage phenotype that was not dependent on or altered by CCL2 co-expression. Together, these data map new binding partners within the TME and demonstrate that whilst the matrix exerts transcriptional control over the chemokine, each plays a distinct role in subverting anti-tumoral immunity.
    Keywords:  CCL2; MCP-1; breast cancer; extracellular matrix; macrophages; myeloid cells; tenascin-C
    DOI:  https://doi.org/10.3390/ijms24098365
  26. Front Oncol. 2023 ;13 1157345
    Antibody-based cancer immunotherapy by targeting regulatory T cells.
    Quanxiao Li, Jun Lu, Jinyao Li, Baohong Zhang, Yanling Wu, Tianlei Ying.
      Regulatory T cells (Tregs) are among the most abundant suppressive cells, which infiltrate and accumulate in the tumor microenvironment, leading to tumor escape by inducing anergy and immunosuppression. Their presence has been correlated with tumor progression, invasiveness and metastasis. Targeting tumor-associated Tregs is an effective addition to current immunotherapy approaches, but it may also trigger autoimmune diseases. The major limitation of current therapies targeting Tregs in the tumor microenvironment is the lack of selective targets. Tumor-infiltrating Tregs express high levels of cell surface molecules associated with T-cell activation, such as CTLA4, PD-1, LAG3, TIGIT, ICOS, and TNF receptor superfamily members including 4-1BB, OX40, and GITR. Targeting these molecules often attribute to concurrent depletion of antitumor effector T-cell populations. Therefore, novel approaches need to improve the specificity of targeting Tregs in the tumor microenvironment without affecting peripheral Tregs and effector T cells. In this review, we discuss the immunosuppressive mechanisms of tumor-infiltrating Tregs and the status of antibody-based immunotherapies targeting Tregs.
    Keywords:  antibody; cancer; immune checkpoint inhibitors; immunotherapy; regulatory (Treg) cell
    DOI:  https://doi.org/10.3389/fonc.2023.1157345
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