bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–12–15
seventeen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Reprogramming the tumor microenvironment - macrophages emerge as key players in breast cancer immunotherapy.
  2. Unveiling the nexus: The tumor microenvironment as a strategic frontier in viral cancers.
  3. Stanniocalcin-1 in tumor immunity: acts via macrophages.
  4. Metabolic reprogramming, sensing, and cancer therapy.
  5. Integrins and Integrin-Driven Secretory Pathways as Multi-dimensional Regulators of Tumor-Associated Macrophage Recruitment and Reprogramming in Tumor Microenvironment.
  6. c-MET and the immunological landscape of cancer: novel therapeutic strategies for enhanced anti-tumor immunity.
  7. CAR-iNKT cell therapy: mechanisms, advantages, and challenges.
  8. Tumor Microenvironment: Nurturing Cancer Cells for Immunoevasion and Druggable Vulnerabilities for Cancer Immunotherapy.
  9. From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape.
  10. Antitumor host immunity enhanced by near-infrared photoimmunotherapy.
  11. Construction of novel magnetic systems for cancer immunotherapy via cancer-immunity cycle circuits.
  12. Soluble CTLA-4 - A confounding factor in CTLA-4 based checkpoint immunotherapy in cancer.
  13. Myriad factors and pathways influencing tumor radiotherapy resistance.
  14. Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review).
  15. IL-17A/CEBPβ/OPN/LYVE-1 axis inhibits anti-tumor immunity by promoting tumor-associated tissue-resident macrophages.
  16. Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment.
  17. Breaking the mold: Unconventional T cells in cancer therapy.
  1. Front Immunol. 2024 ;15 1457491
    Reprogramming the tumor microenvironment - macrophages emerge as key players in breast cancer immunotherapy.
    Ana Sami, Afsheen Raza.
      Breast cancer has the highest global incidence among all cancers, affecting more than 2 million individuals annually. Despite the availability of new drugs and novel treatment combinations, it is postulated that the incidence and mortality of breast cancer will rise by 40.8% and 51.9% respectively by 2040. Such dire statistics are associated with the clonal evolution of cancer cells that leads to therapeutic resistance and consequent relapse in breast cancer patients. On the other hand, the tumor microenvironment (TME) comprising of tumor cells, cancer-associated immune cells, re-programmed stromal cells, and the extracellular matrix (ECM) creates an immunosuppressive niche facilitating immune evasion. This review focuses on a critical cellular component of the tumor microenvironment, the tumor-associated macrophages (TAMs) in breast cancer immunotherapy. Macrophages are inherently plastic and can convert from an anti-tumor M1 phenotype to a pro-tumor M2 phenotype based on microenvironmental cues. Cancer cells facilitate these cues, allowing the tumor-associated macrophages to gain M2 phenotype and mediate immune evasion. Therefore, knowledge of the distinct role of tumor-associated macrophages in immune evasion can help design therapeutics such as engineered macrophages, M2 targeting drugs, and novel macrophage-mediated drug delivery strategies for long-term survival in breast cancer.
    Keywords:  breast cancer; epigenetics; immunotherapy; nanoparticle; tumor microenvironment; tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fimmu.2024.1457491
  2. Cytokine. 2024 Dec 07. pii: S1043-4666(24)00331-4. [Epub ahead of print]185 156827
    Unveiling the nexus: The tumor microenvironment as a strategic frontier in viral cancers.
    Queenie Fernandes, Oginni Gbenga Folorunsho.
      Viral infections are a significant factor in the etiology of various cancers, with the tumor microenvironment (TME) playing a crucial role in disease progression. This review delves into the complex interactions between viruses and the TME, highlighting how these interactions shape the course of viral cancers. We explore the distinct roles of immune cells, including T-cells, B-cells, macrophages, and dendritic cells, within the TME and their influence on cancer progression. The review also examines how viral oncoproteins manipulate the TME to promote immune evasion and tumor survival. Unraveling these mechanisms highlights the emerging paradigm of targeting the TME as a novel approach to cancer treatment. Our analysis provides insights into the dynamic interplay between viruses and the TME, offering a roadmap for innovative treatments that leverage the unique characteristics of viral cancers.
    Keywords:  Cancer immunology; Immunotherapy; Oncoviruses; Therapeutic Cancer vaccines; Tumor microenvironment; Viral cancers
    DOI:  https://doi.org/10.1016/j.cyto.2024.156827
  3. Front Immunol. 2024 ;15 1510182
    Stanniocalcin-1 in tumor immunity: acts via macrophages.
    Lele Wang, Jianjun Wang, Weijie Qiang, Weihong Ge.
      Tumor immune escape has become a research hotspot in the field of cancer immunotherapy. Tumor-associated macrophages (TAMs) are the key component of tumor microenvironment, which play a pivotal role in tumor immune escape by regulating the immunity checkpoints, inhibiting the activity of T lymphocytes and natural killer (NK) cells, and modulating proportion of different T cells. Stanniocalcin-1(STC1)is ubiquitously expressed in human body, which is proven to involve with tumor progression and clinical prognosis. Recently, STC1 is implicated in tumor microenvironment as a phagocytosis checkpoint, as well as regulates the immunity via macrophages. In the review, we discussed the role of STC1 and TAMs in tumor immunity and their crosstalk, hoping to provide references for the research of STC1 in tumor immunotherapy.
    Keywords:  Stanniocalcin-1; immunotherapy; tumor immunity; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2024.1510182
  4. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064
    Metabolic reprogramming, sensing, and cancer therapy.
    Youxiang Mao, Ziyan Xia, Wenjun Xia, Peng Jiang.
      The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.
    Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy
    DOI:  https://doi.org/10.1016/j.celrep.2024.115064
  5. Matrix Biol. 2024 Dec 05. pii: S0945-053X(24)00145-8. [Epub ahead of print]
    Integrins and Integrin-Driven Secretory Pathways as Multi-dimensional Regulators of Tumor-Associated Macrophage Recruitment and Reprogramming in Tumor Microenvironment.
    Nibedita Dalpati, Shubham Kumar Rai, Prerna Sharma, Pranita P Sarangi.
      Integrins, a group of transmembrane receptors, play a crucial role in mediating the interactions between cells and extracellular matrix (ECM) proteins. The intracellular signaling initiated by these cell-matrix interactions in leukocytes mediates many essential cellular processes such as survival, migration, metabolism, and other immunological functions. Macrophages, as phagocytes, participate in both proinflammatory and anti-inflammatory processes, including progression. Numerous reports have shown that the integrin-regulated secretome, comprising cytokines, chemokines, growth factors, proteases, and other bioactive molecules, is a crucial modulator of macrophage functions in tumors, significantly influencing macrophage programming and reprogramming within the tumor microenvironment (TME) in addition to driving their step-by-step entry process into tumor tissue spaces. Importantly, studies have demonstrated a pivotal role for integrin receptor-mediated secretome and associated signaling pathways in functional reprogramming from anti-tumorigenic to pro-tumorigenic phenotype in tumor-associated macrophages (TAMs). In this comprehensive review, we have provided an in-depth analysis of the latest findings of various key pathways, mediators, and signaling cascades associated with integrin-driven polarization of macrophages in tumors. This manuscript will provide an updated understanding of the modulation of inflammatory monocytes/ macrophages and TAMs by integrin-driven secretory pathways in various functions such as migration, differentiation, and their role in tumor progression, angiogenesis, and metastasis.
    Keywords:  Integrins; Monocytes/macrophages; Polarization; Secretome; Tissue-specific infiltration; Tumor-Associated Macrophages; and Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.matbio.2024.12.003
  6. Front Immunol. 2024 ;15 1498391
    c-MET and the immunological landscape of cancer: novel therapeutic strategies for enhanced anti-tumor immunity.
    Parham Jabbarzadeh Kaboli, Ghazaal Roozitalab, Reyhaneh Farghadani, Zoya Eskandarian, Abdessamad Zerrouqi.
      Cellular mesenchymal-epithelial transition factor (c-MET), also known as hepatocyte growth factor receptor (HGFR), is a crucial receptor tyrosine kinase implicated in various solid tumors, including lung, breast, and liver cancers. The concomitant expression of c-MET and PD-L1 in tumors, such as hepatocellular carcinoma, highlights their prognostic significance and connection to therapeutic resistance. Cancer-associated fibroblasts and mesenchymal stromal cells produce hepatocyte growth factor (HGF), activating c-MET signaling in tumor cells and myeloid-derived suppressor cells (MDSC). This activation leads to metabolic reprogramming and increased activity of enzymes like glutaminase (GLS), indoleamine 2,3-dioxygenase (IDO), and arginase 1 (ARG1), depleting essential amino acids in the tumor microenvironment that are vital for effector immune cell function. This review highlights the interplay between tumor cells and myeloid-derived suppressor cells (MDSCs) that create an immunosuppressive environment while providing targets for c-MET-focused immunotherapy. It emphasizes the clinical implications of c-MET inhibition on the behavior of immune cells such as neutrophils, macrophages, T cells, and NK cells. It explores the potential of c-MET antagonism combined with immunotherapeutic strategies to enhance cancer treatment paradigms. This review also discusses the innovative cancer immunotherapies targeting c-MET, including chimeric antigen receptor (CAR) therapies, monoclonal antibodies, and antibody-drug conjugates, while encouraging the development of a comprehensive strategy that simultaneously tackles immune evasion and enhances anti-tumor efficacy further to improve the clinical prognoses for patients with c-MET-positive malignancies. Despite the challenges and variability in efficacy across different cancer subtypes, continued research into the molecular mechanisms and the development of innovative therapeutic strategies will be crucial.
    Keywords:  CAR-T; PD-L1; antibody-drug conjugate; c-MET; cancer; galectin; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1498391
  7. Curr Res Transl Med. 2024 Dec 04. pii: S2452-3186(24)00050-3. [Epub ahead of print]73(1): 103488
    CAR-iNKT cell therapy: mechanisms, advantages, and challenges.
    Zixuan Wang, Guangji Zhang.
      In recent years, chimeric antigen receptor (CAR) T-cell therapy has emerged as a groundbreaking approach in cancer immunotherapy. Particularly in hematologic malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL), B cell lymphomas and multiple myeloma. CAR-T therapy has demonstrated remarkable clinical efficacy, leading to the approval of several CAR-T cell products and offering significant benefits to numerous leukemia patients. Despite these successes, the application of CAR-T cells in solid tumors remains limited due to significant challenges, including immunosuppressive tumor microenvironments, heterogeneous antigen expression, and treatment-associated toxicities. In parallel with CAR-T development, researchers are investigating other immune cell platforms to overcome these obstacles. Among these, invariant natural killer T (iNKT) cells have garnered increasing attention for their unique immunological properties. Unlike conventional T cells, iNKT cells are a subset of T lymphocytes characterized by the expression of a semi-invariant T-cell receptor (TCR) that recognizes lipid antigens presented by CD1d molecules. This distinctive antigen recognition mechanism enables iNKT cells to bridge innate and adaptive immunity, granting them potent antitumor activity and the ability to modulate the tumor microenvironment. Additionally, iNKT cells exhibit intrinsic resistance to exhaustion and an enhanced ability to infiltrate solid tumors compared to traditional T cells. Building on these properties, researchers are leveraging CAR technology to enhance iNKT cell tumor-targeting capabilities, aiming to overcome barriers encountered in solid tumor therapy. This review provides an in-depth discussion of the application and therapeutic potential of CAR-iNKT cells in cancer immunotherapy, with a focus on their advantages over conventional CAR-T cells and their role in addressing the challenges of solid tumor treatment.
    Keywords:  CAR-T; CAR-iNKT; CD1d; Solid tumor; Tumor associated antigen
    DOI:  https://doi.org/10.1016/j.retram.2024.103488
  8. Cancer Lett. 2024 Dec 05. pii: S0304-3835(24)00780-8. [Epub ahead of print] 217385
    Tumor Microenvironment: Nurturing Cancer Cells for Immunoevasion and Druggable Vulnerabilities for Cancer Immunotherapy.
    Hongyang Yu, Jinyang Li, Shiyin Peng, Qin Liu, Dongfeng Chen, Zongsheng He, Junyu Xiang, Bin Wang.
      The tumor microenvironment (TME) is an intricate ecosystem where cancer cells thrive, encompassing a wide array of cellular and non-cellular components. The TME co-evolves with tumor progression in a spatially and temporally dynamic manner, which endows cancer cells with the adaptive capability of evading immune surveillance. To this end, diverse cancer-intrinsic mechanisms were exploited to dampen host immune system, such as upregulating immune checkpoints, impairing antigens presentation and competing for nutrients. In this review, we discuss how cancer immunoevasion is tightly regulated by hypoxia, one of the hallmark biochemical features of the TME. Moreover, we comprehensively summarize how immune evasiveness of cancer cells is facilitated by the extracellular matrix, as well as soluble components of TME, including inflammatory factors, lactate, nutrients and extracellular vesicles. Given their important roles in dictating cancer immunoevasion, various strategies to target TME components are proposed, which holds promising translational potential in developing novel therapeutics to sensitize anti-cancer immunotherapy such as immune checkpoint blockade.
    Keywords:  Immunoevasion; Immunotherapy; Lactate; Nutrients; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.217385
  9. Front Immunol. 2024 ;15 1492050
    From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape.
    Mengqian Jiang, Yuanchun Wang, Xiaoyong Zhao, Jinming Yu.
      Lactic acid, a key metabolic byproduct within the tumor microenvironment, has garnered significant attention for its role in immune evasion mechanisms. Tumor cells produce and release large amounts of lactic acid into the tumor microenvironment through aberrant glycolysis via the Warburg effect, leading to a drop in pH. Elevated lactic acid levels profoundly suppress proliferation capacity, cytotoxic functions, and migratory abilities of immune effector cells such as macrophages and natural killer cells at the tumor site. Moreover, lactic acid can modulate the expression of surface molecules on immune cells, interfering with their recognition and attack of tumor cells, and it regulates signaling pathways that promote the expansion and enhanced function of immunosuppressive cells like regulatory T cells, thereby fostering immune tolerance within the tumor microenvironment. Current research is actively exploring strategies targeting lactic acid metabolism to ameliorate tumor immune evasion. Key approaches under investigation include inhibiting the activity of critical enzymes in lactic acid production to reduce its synthesis or blocking lactate transporters to alter intracellular and extracellular lactate distribution. These methods hold promise when combined with existing immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies to enhance the immune system's ability to eliminate tumor cells. This could pave the way for novel combinatorial treatment strategies in clinical cancer therapy, effectively overcoming tumor immune evasion phenomena, and ultimately improving overall treatment efficacy.
    Keywords:  combination therapy; immune evasion; lactic acid; tumor immune; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1492050
  10. Cancer Sci. 2024 Dec 12.
    Antitumor host immunity enhanced by near-infrared photoimmunotherapy.
    Hiroshi Fukushima, Aki Furusawa, Ryuhei Okada, Yasuhisa Fujii, Peter L Choyke, Hisataka Kobayashi.
      Near-infrared photoimmunotherapy (NIR-PIT) is a novel antitumor therapy that selectively kills cancer cells by NIR light-triggered photochemical reaction of IRDye700DX within Ab-photoabsorber conjugates (APCs). NIR-PIT induces immunogenic cell death, causing immune cell migration between the tumor and tumor-draining lymph nodes, and expanding multiclonal tumor-infiltrating CD8+ T cells. Crucially, the cytotoxic effects of NIR-PIT are limited to cancer cells, sparing immune cells such as antigen-presenting cells and T cells, which are key players in boosting antitumor host immunity. By modifying the Ab used in APC synthesis, NIR-PIT can be repurposed to target and deplete noncancerous immunosuppressive cells including regulatory T cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts in the tumor microenvironment. Immunosuppressive cell targeted NIR-PIT strongly potentiates antitumor host immunity, including the induction of abscopal effects and the development of immune memory. Furthermore, antitumor immune responses and therapeutic efficacy are synergistically enhanced when NIR-PIT is combined with other immune-activating treatments, such as interleukin-15 and immune checkpoint inhibitors. These new findings make NIR-PIT a valuable tool in the evolving landscape of cancer immunotherapy. This review explains the role of NIR-PIT in activating antitumor host immunity.
    Keywords:  antitumor host immunity; cancer; immune cell migration; immunogenic cell death; near‐infrared photoimmunotherapy
    DOI:  https://doi.org/10.1111/cas.16427
  11. J Control Release. 2024 Dec 10. pii: S0168-3659(24)00851-4. [Epub ahead of print]378 38-59
    Construction of novel magnetic systems for cancer immunotherapy via cancer-immunity cycle circuits.
    Linghong Huang, Quan Zhang, Jun Long, Zonghua Liu, Xinyuan Sun.
      The tumor microenvironment (TME) is enriched with immunosuppressive factors that inhibit the recruitment and activation of dendritic cells (DCs), thereby reducing the efficacy of tumor immunotherapy. To address this challenge, we propose an innovative strategy involving the sequential administration of MCM magnetic nanoparticles carrying PROTAC drugs (MCM/ARV) and M-BMDCs in the TEM. This approach not only replenishes DCs in the TEM, but also increases antigen uptake through the attraction between the magnetic particles and promotes DC activation and antigen presentation, thus continuously enhancing the tumor immune cycle. MCM nanoparticles (magnetic nanoclusters coated with calcium-doped manganese carbonate) efficiently load the tumor-targeting drug PROTAC (ARV-825), enhancing its bioavailability, leading to specific degradation of BRD4 in tumor cells, and releasing a large number of tumor-associated antigens. These antigens were captured by MCM nanoparticles to construct magnetized tumor vaccines. Magnetic M-BMDCs introduced at the tumor site are attracted to these magnetized vaccines, resulting in a significant increase in antigen uptake and activation of DCs, significantly enhancing the tumor immune cycle. This co-administration strategy of magnetized vaccines and magnetized BMDCs provides a unique combination therapy for reversing immunosuppressive TEM and enhancing the efficacy of tumor immunotherapy.
    Keywords:  Antigen presentation; Magnetized DCs; Magnetized vaccines; PROTACs
    DOI:  https://doi.org/10.1016/j.jconrel.2024.12.009
  12. Immunol Lett. 2024 Dec 10. pii: S0165-2478(24)00139-1. [Epub ahead of print] 106965
    Soluble CTLA-4 - A confounding factor in CTLA-4 based checkpoint immunotherapy in cancer.
    Parviz Azimnasab-Sorkhabi, Maryam Soltani-Asl, Musab Bouhajra, Ephraim A Ansa-Addo, Jose Roberto Kfoury Junior.
      Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a receptor that inhibits the activity of T cells. The CTLA-4 gene consists of four different exons that enable four different isoforms of CTLA-4 to be generated through alternative splicing. Although sCTLA-4 might impede the therapeutic effect of anti-CTLA-4 treatments, the role of sCTLA-4 in the tumor microenvironment (TME) is not well understood. Here, we provide novel perspectives on the inhibitory characteristics of sCTLA-4 in TME.
    Keywords:  CTLA-4; CTLA-4 isoforms; Immunotherapy(,) Cancer; sCTLA-4
    DOI:  https://doi.org/10.1016/j.imlet.2024.106965
  13. Open Life Sci. 2024 ;19(1): 20220992
    Myriad factors and pathways influencing tumor radiotherapy resistance.
    Lanjuan Mi, Hongquan Zhang.
      Radiotherapy is a cornerstone in the treatment of various tumors, yet radioresistance often leads to treatment failure and tumor recurrence. Several factors contribute to this resistance, including hypoxia, DNA repair mechanisms, and cancer stem cells. This review explores the diverse elements that drive tumor radiotherapy resistance. Historically, resistance has been attributed to cellular repair and tumor repopulation, but recent research has expanded this understanding. The tumor microenvironment - characterized by hypoxia, immune evasion, and stromal interactions - further complicates treatment. Additionally, molecular mechanisms such as aberrant signaling pathways, epigenetic modifications, and non-B-DNA structures play significant roles in mediating resistance. This review synthesizes current knowledge, highlighting the interplay of these factors and their clinical implications. Understanding these mechanisms is crucial for developing strategies to overcome resistance and improve therapeutic outcomes in cancer patients.
    Keywords:  hypoxia; radiotherapy; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.1515/biol-2022-0992
  14. Mol Med Rep. 2025 Feb;pii: 48. [Epub ahead of print]31(2):
    Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review).
    Yi Zeng, Yu Huang, Qiaoyun Tan, Ling Peng, Jian Wang, Fan Tong, Xiaorong Dong.
      Metabolic reprogramming is a prominent characteristic of tumor cells, evidenced by heightened secretion of lactate, which is linked to tumor progression. Furthermore, the accumulation of lactate in the tumor microenvironment (TME) influences immune cell activity, including the activity of macrophages, dendritic cells and T cells, fostering an immunosuppressive milieu. Anti‑programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) therapy is associated with a prolonged survival time of patients with non‑small cell lung cancer. However, some patients still develop resistance to anti‑PD‑1/PD‑L1 therapy. Lactate is associated with resistance to anti‑PD‑1/PD‑L1 therapy. The present review summarizes what is known about lactate metabolism in tumor cells and how it affects immune cell function. In addition, the present review emphasizes the relationship between lactate secretion and immunotherapy resistance. The present review also explores the potential for targeting lactate within the TME to enhance the efficacy of immunotherapy.
    Keywords:  cancer immunity; immunotherapy; lactate; programmed cell death protein 1; programmed death‑ligand 1; tumor environment
    DOI:  https://doi.org/10.3892/mmr.2024.13413
  15. Cell Rep. 2024 Dec 05. pii: S2211-1247(24)01390-1. [Epub ahead of print]43(12): 115039
    IL-17A/CEBPβ/OPN/LYVE-1 axis inhibits anti-tumor immunity by promoting tumor-associated tissue-resident macrophages.
    Lei Zhao, Zonghan Wang, Yuying Tan, Jianan Ma, Wei Huang, Xiaoying Zhang, Chunhui Jin, Ting Zhang, Wentao Liu, Yong-Guang Yang.
      Tumor-associated macrophages (TAMs) are a critical component of the immunosuppressive tumor microenvironment, comprising monocyte-derived macrophages (MDM-TAMs) and tissue-resident macrophages (TRM-TAMs). Here, we discovered that TRM-TAMs mediate the pro-tumor effects of interleukin (IL)-17A and that IL-17A-driven tumor progression requires tumor cell production of osteopontin (OPN). Mechanistically, we identified CEBPβ as a transcription factor downstream of IL-17A in tumor cells and LYVE-1 as an OPN receptor on TRM-TAMs. IL-17A stimulates tumor cell production of OPN, and OPN/LYVE-1 signaling activates the JNK/c-Jun pathway, leading to the proliferation of immunosuppressive LYVE-1+ TRM-TAMs. Unlike its effect on LYVE-1+ TRM-TAMs, OPN interacts with α4β1 to promote the chemotaxis of LYVE-1- MDM-TAMs toward tumors. IL-17A neutralization, OPN inactivation in tumor cells, or LYVE-1 deletion in macrophages inhibited TAMs and enhanced anti-tumor immune responses and anti-PDL1 therapy. Thus, the IL-17A/CEBPβ/OPN/LYVE-1 axis offers a mechanism suppressing anti-tumor immune responses and, hence, an effective therapeutic target for cancer.
    Keywords:  CEBPβ; CP: Cancer; CP: Immunology; IL-17A; LYVE-1; cancer immunotherapy; monocyte-derived macrophage; osteopontin; tissue-resident macrophage; triple-negative breast cancer; tumor microenvironment; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2024.115039
  16. Biochim Biophys Acta Rev Cancer. 2024 Dec 11. pii: S0304-419X(24)00175-6. [Epub ahead of print] 189244
    Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment.
    Helena Branco, Cristina P R Xavier, Chiara Riganti, M Helena Vasconcelos.
      In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.
    Keywords:  Extracellular vesicles; Hypoxia; Intercellular communication; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189244
  17. Cancer Cell. 2024 Dec 06. pii: S1535-6108(24)00445-8. [Epub ahead of print]
    Breaking the mold: Unconventional T cells in cancer therapy.
    Yan-Ruide Li, Kuangyi Zhou, Yichen Zhu, Tyler Halladay, Lili Yang.
      Unconventional T cells, including invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, and mucosal-associated invariant T (MAIT) cells, play important roles in both innate and adaptive immunity. These cells respond to tumors rapidly and influence the tumor microenvironment (TME). Recent advances in understanding their biology, as well as the development of novel therapeutic approaches, have underscored their potential in cancer immunotherapy. This commentary will assess these advances and translational possibilities in the field.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.010
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒15 at 1:06.