bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–03–17
34 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Innate immune cells: Key players of orchestra in modulating tumor microenvironment (TME).
  2. Carbon Ion Irradiation Activates Anti-Cancer Immunity.
  3. The cellular composition of the tumor microenvironment is an important marker for predicting therapeutic efficacy in breast cancer.
  4. The role of ANXA1 in the tumor microenvironment.
  5. Erratum to "Establishment of immune suppression by cancer cells in the tumor microenvironment".
  6. Exosomal ncRNAs: Multifunctional contributors to the immunosuppressive tumor microenvironment of hepatocellular carcinoma.
  7. Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers.
  8. Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors.
  9. Programmed Death Ligand 1 Regulatory Crosstalk with Ubiquitination and Deubiquitination: Implications in Cancer Immunotherapy.
  10. Cancer‑associated fibroblasts under therapy‑induced senescence in the tumor microenvironment (Review).
  11. Ultrasound combined with microbubble mediated immunotherapy for tumor microenvironment.
  12. Intratumoral Delivery of Interleukin 9 via Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in Tumor Models.
  13. Generation of Cancer Stem Cells by Co-Culture Methods.
  14. Editorial: Mechanisms of metastasis from circulating and disseminated tumor cells.
  15. Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy.
  16. LncRNAs act as modulators of macrophages within the tumor microenvironment.
  17. Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.
  18. Role of tumor cell pyroptosis in anti-tumor immunotherapy.
  19. The Killer's Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer.
  20. Metabolism/Immunity Dual-Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate-Excretion Inhibition and PD-1/PD-L1 Blockade.
  21. Editorial: The role of cancer associated fibroblast (CAF) in EMT/metastasis in malignancies of epithelial tissues.
  22. Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.
  23. PGAM1 suppression remodels the tumor microenvironment in triple-negative breast cancer and synergizes with anti-PD-1 immunotherapy.
  24. Exploring the function of myeloid cells in promoting metastasis in head and neck cancer.
  25. Shifting the paradigm: engaging multicellular networks for cancer therapy.
  26. Neutrophils in cancer: dual roles through intercellular interactions.
  27. Mimicking the Tumor Niche: Methods for Isolation, Culture, and Characterization of Cancer Stem Cells and Multicellular Spheroids.
  28. The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling.
  29. Role of STAT3 in pancreatic cancer.
  30. Signaling lymphocytic activation molecule family receptors as potential immune therapeutic targets in solid tumors.
  31. Multicellular Tumoroids for Investigating Cancer Stem-Like Cells in the Heterogeneous Tumor Microenvironment.
  32. Specific lineage transition of tumor-associated macrophages elicits immune evasion of ascitic tumor cells in gastric cancer with peritoneal metastasis.
  33. Editorial: New insights into the role of tumor microbial microenvironment in tumor immunotherapy.
  34. MCT4-driven CAF-mediated metabolic reprogramming in breast cancer microenvironment is a vulnerability targetable by miR-425-5p.
  1. Heliyon. 2024 Mar 15. 10(5): e27480
    Innate immune cells: Key players of orchestra in modulating tumor microenvironment (TME).
    Mahvash Sadeghi, Sajad Dehnavi, Moosa Sharifat, Amir Mohammad Amiri, Ali Khodadadi.
      The tumor microenvironment (TME) with vital role in cancer progression is composed of various cells such as endothelial cells, immune cells, and mesenchymal stem cells. In particular, innate immune cells such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, innate lymphoid cells, γδT lymphocytes, and natural killer cells can either promote or suppress tumor progression when present in the TME. An increase in research on the cross-talk between the TME and innate immune cells will lead to new approaches for anti-tumoral therapeutic interventions. This review primarily focuses on the biology of innate immune cells and their main functions in the TME. In addition, it summarizes several innate immune-based immunotherapies that are currently tested in clinical trials.
    Keywords:  Anti-tumor treatment; Immunotherapy; Innate immune cells; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e27480
  2. Int J Mol Sci. 2024 Feb 29. pii: 2830. [Epub ahead of print]25(5):
    Carbon Ion Irradiation Activates Anti-Cancer Immunity.
    Makoto Sudo, Hiroko Tsutsui, Jiro Fujimoto.
      Carbon ion beams have the unique property of higher linear energy transfer, which causes clustered damage of DNA, impacting the cell repair system. This sometimes triggers apoptosis and the release in the cytoplasm of damaged DNA, leading to type I interferon (IFN) secretion via the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Dendritic cells phagocytize dead cancer cells and damaged DNA derived from injured cancer cells, which together activate dendritic cells to present cancer-derived antigens to antigen-specific T cells in the lymph nodes. Thus, carbon ion radiation therapy (CIRT) activates anti-cancer immunity. However, cancer is protected by the tumor microenvironment (TME), which consists of pro-cancerous immune cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The TME is too robust to be destroyed by the CIRT-mediated anti-cancer immunity. Various modalities targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages have been developed. Preclinical studies have shown that CIRT-mediated anti-cancer immunity exerts its effects in the presence of these modalities. In this review article, we provide an overview of CIRT-mediated anti-cancer immunity, with a particular focus on recently identified means of targeting the TME.
    Keywords:  anti-cancer immunity; cancer immunosurveillance; carbon ion radiotherapy (CIRT); myeloid-derived suppressor cells (MDSCs); regulatory T cells (Tregs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/ijms25052830
  3. Front Immunol. 2024 ;15 1368687
    The cellular composition of the tumor microenvironment is an important marker for predicting therapeutic efficacy in breast cancer.
    Tingyao Dou, Jing Li, Yaochen Zhang, Wanru Pei, Binyue Zhang, Bin Wang, Yanhong Wang, Hongyan Jia.
      At present, the incidence rate of breast cancer ranks first among new-onset malignant tumors in women. The tumor microenvironment is a hot topic in tumor research. There are abundant cells in the tumor microenvironment that play a protumor or antitumor role in breast cancer. During the treatment of breast cancer, different cells have different influences on the therapeutic response. And after treatment, the cellular composition in the tumor microenvironment will change too. In this review, we summarize the interactions between different cell compositions (such as immune cells, fibroblasts, endothelial cells, and adipocytes) in the tumor microenvironment and the treatment mechanism of breast cancer. We believe that detecting the cellular composition of the tumor microenvironment is able to predict the therapeutic efficacy of treatments for breast cancer and benefit to combination administration of breast cancer.
    Keywords:  breast cancer; combination administration; immune cell; treatment mechanism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1368687
  4. Int Immunopharmacol. 2024 Mar 12. pii: S1567-5769(24)00372-2. [Epub ahead of print]131 111854
    The role of ANXA1 in the tumor microenvironment.
    Lanxin Li, Baiqi Wang, Shuang Zhao, Qinglin Xiong, Ailan Cheng.
      Annexin A1 (ANXA1) is widely expressed in a variety of body tissues and cells and is also involved in tumor development through multiple pathways. The invasion, metastasis, and immune escape of tumor cells depend on the interaction between tumor cells and their surrounding environment. Research shows that ANXA1 can act on a variety of cells in the tumor microenvironment (TME), and subsequently affect the proliferation, invasion and metastasis of tumors. This article describes the role of ANXA1 in the various components of the tumor microenvironment and its mechanism of action, as well as the existing clinical treatment measures related to ANXA1. These findings provide insight for the further design of strategies targeting ANXA1 for the diagnosis and treatment of malignant tumors.
    Keywords:  Angiogenesis; AnnexinA1; Immune; Inflammation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.111854
  5. Proc Jpn Acad Ser B Phys Biol Sci. 2024 ;100(3): 252
    Erratum to "Establishment of immune suppression by cancer cells in the tumor microenvironment".
    Hiroyoshi Nishikawa.
      
    DOI:  https://doi.org/10.2183/pjab.100.016
  6. Biomed Pharmacother. 2024 Mar 08. pii: S0753-3322(24)00293-2. [Epub ahead of print]173 116409
    Exosomal ncRNAs: Multifunctional contributors to the immunosuppressive tumor microenvironment of hepatocellular carcinoma.
    Qi Huang, Xin Zhong, Jing Li, Rui Hu, Jinyu Yi, Jialing Sun, Youhua Xu, Xiaozhou Zhou.
      Hepatocellular carcinoma (HCC) is a malignant liver cancer characterized by aggressive progression, unfavorable prognosis, and an increasing global health burden. Therapies that precisely target immunological checkpoints and immune cells have gained significant attention as possible therapeutics in recent years. In truth, the efficacy of immunotherapy is heavily contingent upon the tumor microenvironment (TME). Recent studies have indicated that exosomes serve as a sophisticated means of communication among biomolecules, executing an essential part in the TME of immune suppression. Exosomal non-coding RNAs (ncRNAs) can induce the activation of tumor cells and immunosuppressive immune cells that suppress the immune system, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), CD+8 T cells, regulatory T cells (Tregs), and regulatory B cells (Bregs). This cell-cell crosstalk triggered by exosomal ncRNAs promotes tumor proliferation and metastasis, angiogenesis, malignant phenotype transformation, and drug resistance. Hence, it is imperative to comprehend how exosomal ncRNAs regulate tumor cells or immune cells within the TME to devise more comprehensive and productive immunotherapy programs. This study discusses the features of exosomal ncRNAs in HCC and how the activation of the exosomes redefines the tumor's immunosuppressive microenvironment, hence facilitating the advancement of HCC. Furthermore, we also explored the potential of exosomal ncRNAs as a viable biological target or natural vehicle for HCC therapy.
    Keywords:  Exosomes; Hepatocellular carcinoma; Immunosuppression; Non-coding RNAs; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2024.116409
  7. Int J Mol Sci. 2024 Mar 04. pii: 2985. [Epub ahead of print]25(5):
    Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers.
    Junaid Arshad, Amith Rao, Matthew L Repp, Rohit Rao, Clinton Wu, Juanita L Merchant.
      Gastrointestinal cancers represent one of the more challenging cancers to treat. Current strategies to cure and control gastrointestinal (GI) cancers like surgery, radiation, chemotherapy, and immunotherapy have met with limited success, and research has turned towards further characterizing the tumor microenvironment to develop novel therapeutics. Myeloid-derived suppressor cells (MDSCs) have emerged as crucial drivers of pathogenesis and progression within the tumor microenvironment in GI malignancies. Many MDSCs clinical targets have been defined in preclinical models, that potentially play an integral role in blocking recruitment and expansion, promoting MDSC differentiation into mature myeloid cells, depleting existing MDSCs, altering MDSC metabolic pathways, and directly inhibiting MDSC function. This review article analyzes the role of MDSCs in GI cancers as viable therapeutic targets for gastrointestinal malignancies and reviews the existing clinical trial landscape of recently completed and ongoing clinical studies testing novel therapeutics in GI cancers.
    Keywords:  CCR5; CXCR2; IDO-1; MDSC; PDE; gastrointestinal cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25052985
  8. Front Oncol. 2024 ;14 1374742
    Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors.
    Longyang Cao, Hong Ouyang.
      Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, and lipids and can serve as messengers for intercellular communication. They play critical roles in the exchange of information between tumor cells and the tumor microenvironment (TME). The TME consists of mesenchymal cells and components of the extracellular matrix (ECM), with fibroblasts being the most abundant cell type in the tumor mesenchyme. Cancer-associated fibroblasts (CAFs) are derived from normal fibroblasts and mesenchymal stem cells that are activated in the TME. CAFs can secrete exosomes to modulate cell proliferation, invasion, migration, drug resistance, and other biological processes in tumors. Additionally, tumor cells can manipulate the function and behavior of fibroblasts through direct cell-cell interactions. This review provides a summary of the intercellular crosstalk between GI tumor cells and CAFs through exosomes, along with potential underlying mechanisms.
    Keywords:  cancer-associated fibroblasts (CAFs); exosomes; gastrointestinal (GI) tumors; review; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2024.1374742
  9. Int J Mol Sci. 2024 Mar 03. pii: 2939. [Epub ahead of print]25(5):
    Programmed Death Ligand 1 Regulatory Crosstalk with Ubiquitination and Deubiquitination: Implications in Cancer Immunotherapy.
    Soon-Bin Kim, Soonjae Hwang, Ji-Young Cha, Ho-Jae Lee.
      Programmed death ligand 1 (PD-L1) plays a pivotal role in cancer immune evasion and is a critical target for cancer immunotherapy. This review focuses on the regulation of PD-L1 through the dynamic processes of ubiquitination and deubiquitination, which are crucial for its stability and function. Here, we explored the intricate mechanisms involving various E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) that modulate PD-L1 expression in cancer cells. Specific ligases are discussed in detail, highlighting their roles in tagging PD-L1 for degradation. Furthermore, we discuss the actions of DUBs that stabilize PD-L1 by removing ubiquitin chains. The interplay of these enzymes not only dictates PD-L1 levels but also influences cancer progression and patient response to immunotherapies. Furthermore, we discuss the therapeutic implications of targeting these regulatory pathways and propose novel strategies to enhance the efficacy of PD-L1/PD-1-based therapies. Our review underscores the complexity of PD-L1 regulation and its significant impact on the tumor microenvironment and immunotherapy outcomes.
    Keywords:  PD-L1; PTM; deubiquitination; immunotherapy; ubiquitination
    DOI:  https://doi.org/10.3390/ijms25052939
  10. Exp Ther Med. 2024 Apr;27(4): 150
    Cancer‑associated fibroblasts under therapy‑induced senescence in the tumor microenvironment (Review).
    Qiuhua Zhang, Yijie Lou, Hao Fang, Shaopeng Sun, Rijuan Jin, Yunxi Ji, Zhe Chen.
      Current cancer treatments target tumor cells; however, the tumor microenvironment (TME) induces therapeutic resistance, tumor development and metastasis, thus rendering these treatments ineffective. Research on the TME has therefore concentrated on nonmalignant cells. Cancer-associated fibroblasts (CAFs) are a major TME component, which contribute to cancer progression due to their diverse origins, phenotypes and functions, including cancer cell invasion and migration, extracellular matrix remodeling, tumor metabolism modulation and therapeutic resistance. Standard cancer treatment typically exacerbates the senescence-associated secretory phenotype (SASP) of senescent cancer cells and nonmalignant cells that actively leak proinflammatory signals in the TME. Therapy-induced senescence may impair cancer cell activity and compromise treatment responsiveness. CAFs and SASP are well-studied in the formation and progression of cancer. The present review discusses the current data on CAF senescence caused by anticancer treatment and assesses how senescence-like CAFs affect tumor formation. The development of senolytic medication for aging stromal cells is also highlighted. Combining cancer therapies with senolytics may boost therapeutic effects and provide novel possibilities for research.
    Keywords:  CAFs; TIS; TME; cancer; therapeutic resistance
    DOI:  https://doi.org/10.3892/etm.2024.12438
  11. Front Pharmacol. 2024 ;15 1304502
    Ultrasound combined with microbubble mediated immunotherapy for tumor microenvironment.
    Yunfeng Wu, Jiajia Li, Linfeng Shu, Zhaoyu Tian, Siru Wu, Zuohui Wu.
      The tumor microenvironment (TME) plays an important role in dynamically regulating the progress of cancer and influencing the therapeutic results. Targeting the tumor microenvironment is a promising cancer treatment method in recent years. The importance of tumor immune microenvironment regulation by ultrasound combined with microbubbles is now widely recognized. Ultrasound and microbubbles work together to induce antigen release of tumor cell through mechanical or thermal effects, promoting antigen presentation and T cells' recognition and killing of tumor cells, and improve tumor immunosuppression microenvironment, which will be a breakthrough in improving traditional treatment problems such as immune checkpoint blocking (ICB) and himeric antigen receptor (CAR)-T cell therapy. In order to improve the therapeutic effect and immune regulation of TME targeted tumor therapy, it is necessary to develop and optimize the application system of microbubble ultrasound for organs or diseases. Therefore, the combination of ultrasound and microbubbles in the field of TME will continue to focus on developing more effective strategies to regulate the immunosuppression mechanisms, so as to activate anti-tumor immunity and/or improve the efficacy of immune-targeted drugs, At present, the potential value of ultrasound combined with microbubbles in TME targeted therapy tumor microenvironment targeted therapy has great potential, which has been confirmed in the experimental research and application of breast cancer, colon cancer, pancreatic cancer and prostate cancer, which provides a new alternative idea for clinical tumor treatment. This article reviews the research progress of ultrasound combined with microbubbles in the treatment of tumors and their application in the tumor microenvironment.
    Keywords:  cavitation effect; immunotherapy; tumor cell; tumour microenvironment; ultrasound
    DOI:  https://doi.org/10.3389/fphar.2024.1304502
  12. Cancers (Basel). 2024 Feb 29. pii: 1021. [Epub ahead of print]16(5):
    Intratumoral Delivery of Interleukin 9 via Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in Tumor Models.
    Junjie Ye, Lingjuan Chen, Julia Waltermire, Jinshun Zhao, Jinghua Ren, Zongsheng Guo, David L Bartlett, Zuqiang Liu.
      The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4+ and CD8+ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy.
    Keywords:  IL-10; IL-9; anti-CTLA-4 antibody; colon cancer; combination; immune checkpoint blockade; immunotherapy; modulation; oncolytic virus; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16051021
  13. Methods Mol Biol. 2024 ;2777 219-230
    Generation of Cancer Stem Cells by Co-Culture Methods.
    Biswajit Das, Chanakya Nath Kundu.
      Cancer stem cells (CSCs) exhibit intricate regulatory dynamics within the tumor microenvironment, involving interactions with various components like mesenchymal stem cells (MSCs), adipocytes, cancer-associated fibroblasts (CAFs), endothelial cells, tumor-associated macrophages (TAMs), and other immune cells. These interactions occur through complex networks of cytokines, inflammatory factors, and several growth factors. Diverse techniques are employed to generate CSCs, including serum-free sphere culture, chemotherapy, and radiation therapy. A novel approach to generate CSCs involves co-culturing, wherein recent research highlights the role of secreted factors such as inflammatory cytokines from MSCs, CAFs, and TAMs in inducing CSC-like characteristics in cancer cells. While the co-culture method shows promise in generating CSCs, further investigations are needed to comprehensively establish this process. This chapter focuses on establishing a co-culture-based technique for generating CSCs by combining cancer cells with TAMs and CAFs, elucidating the intricate mechanisms underlying this phenomenon.
    Keywords:  Cancer associated fibroblasts; Cancer cells; Cancer stem cells; Co-culture; Tumor associated macrophages
    DOI:  https://doi.org/10.1007/978-1-0716-3730-2_16
  14. Front Cell Dev Biol. 2024 ;12 1386050
    Editorial: Mechanisms of metastasis from circulating and disseminated tumor cells.
    Roberto Piñeiro.
      
    Keywords:  cancer-associated fibroblasts (CAFs); circulating tumor cells (CTCs); disseminated tumor cells (DTCs); liquid biopsy; metastasis; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2024.1386050
  15. Cell Commun Signal. 2024 Mar 11. 22(1): 173
    Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy.
    Shengzhe Jin, Hongfei Wang, Yang Li, Jingwen Yang, Beibei Li, Peishang Shi, Xiangrui Zhang, Xiaowen Zhou, Xiuman Zhou, Xiaoshuang Niu, Menghan Wu, Yahong Wu, Wenjie Zhai, Yuanming Qi, Yanfeng Gao, Wenshan Zhao.
       BACKGROUND: Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative.
    METHODS: SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model.
    RESULTS: SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8+ T and M1-type macrophages into tumor sites, while also priming the function of CD8+ T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy.
    CONCLUSION: Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy.
    Keywords:  CD47/SIRPα; Immune checkpoint blockade; PD-1/PD-L1; Radiotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12964-024-01555-4
  16. Carcinogenesis. 2024 Mar 09. pii: bgae021. [Epub ahead of print]
    LncRNAs act as modulators of macrophages within the tumor microenvironment.
    Kangning Li, Tao Xie, Yong Li, Xuan Huang.
      Long non-coding RNAs (lncRNAs) have been established as pivotal players in various cellular processes, encompassing the regulation of transcription, translation, post-translational modulation of proteins, thereby influencing cellular functions. Notably, lncRNAs exert a regulatory influence on diverse biological processes, particularly in the context of tumor development. Tumor-associated macrophages (TAMs) exhibit the M2 phenotype, exerting significant impact on crucial processes such as tumor initiation, angiogenesis, metastasis, and immune evasion. Elevated infiltration of TAMs into the tumor microenvironment (TME) is closely associated with a poor prognosis in various cancers. LncRNAs within TAMs play a direct role in regulating cellular processes. Functioning as integral components of tumor-derived exosomes, lncRNAs prompt the M2-like polarization of macrophages. Concurrently, reports indicate that lncRNAs in tumor cells contribute to the expression and release of molecules that modulate TAMs within the TME. These actions of lncRNAs induce the recruitment, infiltration, and M2 polarization of TAMs, thereby providing critical support for tumor development. In this review, we survey recent studies elucidating the impact of lncRNAs on macrophage recruitment, polarization, and function across different types of cancers.
    Keywords:  cancers; lncRNA; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.1093/carcin/bgae021
  17. Res Sq. 2024 Feb 22. pii: rs.3.rs-3959342. [Epub ahead of print]
    Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.
    Hasan Korkaya, Fulya Koksalar Alkan, Ahmet Caglayan, Hilmi Alkan, Elayne Benson, Yunus Gunduz, Ozge Sensoy, Serdar Durdagi, Elbrus Zarbaliyev, Gregory Dyson, Hadeel Assad, Austin Shull, Ahmed Chadli, Huidong Shi, Gurkan Ozturk.
      Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.
    DOI:  https://doi.org/10.21203/rs.3.rs-3959342/v1
  18. Cell Insight. 2024 Jun;3(3): 100153
    Role of tumor cell pyroptosis in anti-tumor immunotherapy.
    Lincheng Zhang, Haotian Bai, Jing Zhou, Lilin Ye, Leiqiong Gao.
      Peripheral tumor-specific CD8+ T cells often fail to infiltrate into tumor parenchyma due to the immunosuppression of tumor microenvironment (TME). Meanwhile, a significant portion of tumor-specific CD8+ T cells infiltrated into TME are functionally exhausted. Despite the enormous success of anti-PD-1/PD-L1 immune-checkpoint blockade (ICB) treatment in a wide variety of cancer types, the majority of patients do not respond to this treatment largely due to the failure to efficiently drive tumor-specific CD8+ T cell infiltration and reverse their exhaustion states. Nowadays, tumor cell pyroptosis, a unique cell death executed by pore-forming gasdermin (GSDM) family proteins dependent or independent on inflammatory caspase activation, has been shown to robustly promote immune-killing of tumor cells by enhancing tumor immunogenicity and altering the inflammatory state in the TME, which would be beneficial in overcoming the shortages of anti-PD-1/PD-L1 ICB therapy. Therefore, in this review we summarize the current progresses of tumor cell pyroptosis in enhancing immune function and modulating TME, which synergizes anti-PD-1/PD-L1 ICB treatment to achieve better anti-tumor effect. We also enumerate several strategies to better amply the efficiency of anti-PD-1/PD-L1 ICB therapy by inducing tumor cell pyroptosis.
    Keywords:  Anti-PD-1/PD-L1 ICB; Immunotherapy; Tumor cell pyroptosis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellin.2024.100153
  19. Int J Mol Sci. 2024 Feb 27. pii: 2750. [Epub ahead of print]25(5):
    The Killer's Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer.
    Marisabel Mecca, Simona Picerno, Salvatore Cortellino.
      Inflammation is a key contributor to both the initiation and progression of tumors, and it can be triggered by genetic instability within tumors, as well as by lifestyle and dietary factors. The inflammatory response plays a critical role in the genetic and epigenetic reprogramming of tumor cells, as well as in the cells that comprise the tumor microenvironment. Cells in the microenvironment acquire a phenotype that promotes immune evasion, progression, and metastasis. We will review the mechanisms and pathways involved in the interaction between tumors, inflammation, and nutrition, the limitations of current therapies, and discuss potential future therapeutic approaches.
    Keywords:  DNA repair; cancer; epigenetic; inflammation; nutrition
    DOI:  https://doi.org/10.3390/ijms25052750
  20. Adv Sci (Weinh). 2024 Mar 09. e2310163
    Metabolism/Immunity Dual-Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate-Excretion Inhibition and PD-1/PD-L1 Blockade.
    Tianliang Li, Dan Xu, Zhao Ruan, Jie Zhou, Wenbo Sun, Bo Rao, Haibo Xu.
      Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient tumor infiltration of T cells severely impede the progress of glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting the expression of glucose transporter 1 (GLUT1) can facilitate the prevention of lactate excretion from tumor glycolysis, which significantly alleviates the lactate-driven ITM by reducing immunosuppressive tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). Simultaneously, the findings show that the generated inflammatory cytokine IFN-γ during immune activation aggravates the immune escape by upregulating immune checkpoint programmed death-ligand 1 (PD-L1) in tumor cells and TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY-876 and a PD-1/PD-L1 blocker BMS-1 (Gel@B-B) for dual-regulation of metabolism and immunity of GBM is developed. Consequently, in situ injection of Gel@B-B significantly delays tumor growth and prolongs the survival of the orthotopic GBM mouse model. By actively exposing tumor antigens to antigen-presenting cells, the GBM vaccine combined with Gel@B-B is found to significantly increase the fraction of effector T cells (Th1/CTLs) in the tumor microenvironment, thereby remarkably mitigating tumor recurrence long-term. This study may provide a promising strategy for GBM immunotherapy.
    Keywords:  drug-loading thermogels; glioblastoma; immune checkpoint; lactate; vaccines
    DOI:  https://doi.org/10.1002/advs.202310163
  21. Front Cell Dev Biol. 2024 ;12 1384150
    Editorial: The role of cancer associated fibroblast (CAF) in EMT/metastasis in malignancies of epithelial tissues.
    Biplab Giri, Tapasree Roy Sarkar.
      
    Keywords:  breast cancer; cancer associated fibroblast (CAF); extracellular vesicles (EVs); metastasis; notch signaling in TME; oral squamous cell carcinoma (OSCC); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2024.1384150
  22. Int J Biol Sci. 2024 ;20(5): 1884-1904
    Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.
    Jia Wang, Wenfeng Zhang, Cun Liu, LongYun Wang, Jibiao Wu, Changgang Sun, Qibiao Wu.
      Due to the unique characteristics of breast cancer initiation sites and significant alterations in tumor metabolism, breast cancer cells rely on lipid metabolic reprogramming to effectively regulate metabolic programs during the disease progression cascade. This adaptation enables them to meet the energy demands required for proliferation, invasion, metastasis, and responses to signaling molecules in the breast cancer microenvironment. In this review, we comprehensively examined the distinctive features of lipid metabolic reprogramming in breast cancer and elucidated the underlying mechanisms driving aberrant behavior of tumor cells. Additionally, we emphasize the potential role and adaptive changes in lipid metabolism within the breast cancer microenvironment, while summarizing recent preclinical studies. Overall, precise control over lipid metabolism rewiring and understanding of plasticity within the breast cancer microenvironment hold promising implications for developing targeted treatment strategies against this disease. Therefore, interventions targeting the lipid metabolism in breast cancer may facilitate innovative advancements in clinical applications.
    Keywords:  Breast cancer; Lipid metabolism; Targeted intervention; Tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.92125
  23. J Leukoc Biol. 2024 Mar 13. pii: qiae065. [Epub ahead of print]
    PGAM1 suppression remodels the tumor microenvironment in triple-negative breast cancer and synergizes with anti-PD-1 immunotherapy.
    Dong Zhang, Min Wang, Wenying Wang, Shiya Ma, Wenwen Yu, Xiubao Ren, Qian Sun.
      Triple-negative breast cancer (TNBC) is a high-risk form of breast cancer with a high metastatic potential and lack of effective therapies. Immunotherapy has shown encouraging clinical benefits, and its efficacy in TNBC is affected by immunocyte infiltration in the tumor microenvironment (TME). Phosphoglycerate mutase 1 (PGAM1) is a key enzyme involved in cancer metabolism; however, its role in the TME remains unclear. In this study, we aimed to investigate the role of PGAM1 in TNBC and determine the potential of PGAM1 inhibition in combination with anti-PD-1 immunotherapy. Our results showed that PGAM1 is highly expressed in TNBC and is associated with poor prognosis. In vivo experiments demonstrated that PGAM1 inhibition synergizes with anti-PD-1 immunotherapy, significantly remodeling the TME and leading to an increase in anti-tumor immunocytes, such as CD8+ T cells and M1-macrophages, and a reduction in immunosuppressive cell infiltration, including myeloid-derived suppressor cells, M2-macrophage, and Tregs. Functional and animal experiments showed that this synergistic mechanism inhibited tumor growth in vitro and in vivo. We identified PGAM1 as a novel target that exhibits an antitumor effect via the regulation of immunocyte infiltration. Our results show that PGAM1 can synergize with anti-PD-1 immunotherapy, providing a novel treatment strategy for TNBC.
    Keywords:  PGAM1; TME; Triple-negative breast cancer; anti-PD-1 immunotherapy
    DOI:  https://doi.org/10.1093/jleuko/qiae065
  24. Explor Target Antitumor Ther. 2024 ;5(1): 108-119
    Exploring the function of myeloid cells in promoting metastasis in head and neck cancer.
    Dakota Dike Dimegwu Okwuone, Deri Morgan, Gregory N Gan.
      Head and neck cancer (HNC) is a challenging disease that lacks effective treatment, particularly in the cases that spread locoregionally and metastasize distantly, dramatically reducing patient survival rates. Expanding the understanding of the mechanisms of the metastatic cascade is critical for creating more effective therapeutics that improve outcomes for HNC patients. A true grasp of cancer metastasis requires the consideration of all cell types that contribute to the inflammatory HNC microenvironment as drivers of this process. More emphasis now is being placed on exploring the roles of the different immune cells in cancer control, tumorigenesis and metastasis. Myeloid cells are the most numerous immune cell types in the body, and they are actively recruited and reprogrammed by tumor cells to behave in a variety of ways. These cells are remarkably diverse in phenotype and function, and the part they play in tumor spread greatly differs based on the cell type. This review will focus on summarizing the roles of macrophages, neutrophils, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs) in driving HNC metastasis by examining the current knowledge base and offering potential new routes through which to target and treat this deadly process.
    Keywords:  Head and neck cancer; dendritic cells; immunology; macrophages; metastasis; neutrophils; tumor microenvironment
    DOI:  https://doi.org/10.37349/etat.2024.00208
  25. J Transl Med. 2024 Mar 12. 22(1): 270
    Shifting the paradigm: engaging multicellular networks for cancer therapy.
    Joyce Hu, Paolo Ascierto, Alessandra Cesano, Volker Herrmann, Francesco M Marincola.
      Most anti-cancer modalities are designed to directly kill cancer cells deploying mechanisms of action (MOAs) centered on the presence of a precise target on cancer cells. The efficacy of these approaches is limited because the rapidly evolving genetics of neoplasia swiftly circumvents the MOA generating therapy-resistant cancer cell clones. Other modalities engage endogenous anti-cancer mechanisms by activating the multi-cellular network (MCN) surrounding neoplastic cells in the tumor microenvironment (TME). These modalities hold a better chance of success because they activate numerous types of immune effector cells that deploy distinct cytotoxic MOAs. This in turn decreases the chance of developing treatment-resistance. Engagement of the MCN can be attained through activation of immune effector cells that in turn kill cancer cells or when direct cancer killing is complemented by the production of proinflammatory factors that secondarily recruit and activate immune effector cells. For instance, adoptive cell therapy (ACT) supplements cancer cell killing with the release of homeostatic and pro-inflammatory cytokines by the immune cells and damage associated molecular patterns (DAMPs) by dying cancer cells. The latter phenomenon, referred to as immunogenic cell death (ICD), results in an exponential escalation of anti-cancer MOAs at the tumor site. Other approaches can also induce exponential cancer killing by engaging the MCN of the TME through the release of DAMPs and additional pro-inflammatory factors by dying cancer cells. In this commentary, we will review the basic principles that support emerging paradigms likely to significantly improve the efficacy of anti-cancer therapy.
    DOI:  https://doi.org/10.1186/s12967-024-05043-8
  26. Oncogene. 2024 Mar 12.
    Neutrophils in cancer: dual roles through intercellular interactions.
    Xinyu Yu, Changhui Li, Zijin Wang, Yaping Xu, Shiqun Shao, Fangwei Shao, Hua Wang, Jian Liu.
      Neutrophils, the most abundant immune cells in human blood, play crucial and diverse roles in tumor development. In the tumor microenvironment (TME), cancer cells regulate the recruitment and behaviors of neutrophils, transforming some of them into a pro-tumor phenotype. Pro-tumor neutrophils interact with cancer cells in various ways to promote cancer initiation, growth, and metastasis, while anti-tumor neutrophils interact with cancer cells to induce senescence and death. Neutrophils can also interact with other cells in TME, including T cells, macrophages, stromal cells, etc. to exert anti- or pro-tumor functions. In this review, we will analyze the anti- and pro-tumor intercellular interactions mediated by neutrophils, with a focus on generalizing the mechanisms underlying the interaction of neutrophils with tumor cells and T cells. Furthermore, we will provide an overview of cancer treatment strategies targeting neutrophil-mediated cellular interactions.
    DOI:  https://doi.org/10.1038/s41388-024-03004-5
  27. Methods Mol Biol. 2024 ;2777 145-161
    Mimicking the Tumor Niche: Methods for Isolation, Culture, and Characterization of Cancer Stem Cells and Multicellular Spheroids.
    Laura De Lara-Peña, Cristiano Farace, Andrea Pisano, Julia López de Andrés, Grazia Fenu, Federica Etzi, Carmen Griñán-Lisón, Juan Antonio Marchal, Roberto Madeddu.
      Cancer stem cells (CSCs) play a significant role in driving several tumor hallmarks. Their behavior and tumor progression are strictly related to the tumor microenvironment (TME). The dynamic interplay between CSCs and TME drives metastasis, chemoresistance, and disease relapse. In this chapter, we describe different techniques and protocols for isolating, culturing, and characterizing CSCs and we explain the methodology for the culture of multicellular spheroids comprising CSCs.
    Keywords:  3D cultures; CSC characterization; CSC markers; CSC niche; Cancer stem cells (CSCs); Tumorspheres; Tumour
    DOI:  https://doi.org/10.1007/978-1-0716-3730-2_11
  28. Cell Commun Signal. 2024 Mar 12. 22(1): 179
    The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling.
    Tianye Li, Mengke Niu, Jianwei Zhou, Kongming Wu, Ming Yi.
      The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become a focal point in cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result in T cell exhaustion and immune evasion, fostering tumor progression. The advent of PD-1/PD-L1 inhibitor has demonstrated clinical success by unleashing T cells from exhaustion. Nevertheless, challenges such as resistance and adverse effects have spurred the exploration of innovative strategies, with bispecific antibodies (BsAbs) emerging as a promising frontier. BsAbs offer a multifaceted approach to cancer immunotherapy by simultaneously targeting PD-L1 and other immune regulatory molecules. We focus on recent advancements in PD-1/PD-L1 therapy with a particular emphasis on the development and potential of BsAbs, especially in the context of solid tumors. Various BsAb products targeting PD-1 signaling are discussed, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFβ × PD-L1, anti-CD47 × PD-L1, anti-VEGF × PD-L1, anti-4-1BB × PD-L1, anti-LAG-3 × PD-L1, and anti-PD-1 × CTLA-4 BsAbs. Besides, we summarize ongoing clinical studies evaluating the efficacy and safety of these innovative BsAb agents. By unraveling the intricacies of the tumor microenvironment and harnessing the synergistic effects of anti-PD-1/PD-L1 BsAbs, there exists the potential to elevate the precision and efficacy of cancer immunotherapy, ultimately enabling the development of personalized treatment strategies tailored to individual patient profiles.
    Keywords:  4-1BB; Bispecific antibody; CD47; Cancer immunotherapy; PD-1; PD-L1; TGFβ; VEGF
    DOI:  https://doi.org/10.1186/s12964-024-01562-5
  29. Explor Target Antitumor Ther. 2024 ;5(5): 20-34
    Role of STAT3 in pancreatic cancer.
    Zachary Hamel, Sierra Sanchez, David Standing, Shrikant Anant.
      Pancreatic cancer remains a serious and deadly disease, impacting people globally. There remain prominent gaps in the current understanding of the disease, specifically regarding the role of the signal transducer and activator of transcription (STAT) family of proteins in pancreatic tumors. STAT proteins, particularly STAT3, play important roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), which is the most prevalent histotype. The role of STAT3 across a continuum of molecular processes, such as PDAC tumorigenesis and progression, immune escape, drug resistance and stemness, and modulation of the tumor microenvironment (TME), are only a tip of the iceberg. In some ways, the role of STAT3 in PDAC may hold greater importance than that of oncogenic Kirsten rat sarcoma virus (KRAS). This makes STAT3 a highly attractive target for developing targeted therapies for the treatment of pancreatic cancer. In this review, the current knowledge of STAT3 in pancreatic cancer has been summarized, particularly relating to STAT3 activation in cancer cells, cells of the TME, and the state of targeting STAT3 in pre-clinical and clinical trials of PDAC.
    Keywords:  Signal transducer and activator of transcription; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.37349/etat.2024.00202
  30. Front Immunol. 2024 ;15 1297473
    Signaling lymphocytic activation molecule family receptors as potential immune therapeutic targets in solid tumors.
    Metin Gunes, Steven T Rosen, Idit Shachar, E Gulsen Gunes.
      Recently, cancer immunotherapy has revolutionized cancer treatment. Various forms of immunotherapy have a manageable safety profile and result in prolongation of overall survival in patients with solid tumors, but only in a proportion of patients. Various factors in the tumor microenvironment play critical roles and may be responsible for this lack of therapeutic response. Signaling lymphocytic activation molecule family (SLAMF) members are increasingly being studied as factors impacting the tumor immune microenvironment. SLAMF members consist of nine receptors mainly expressed in immune cells. However, SLAMF receptors have also been detected in cancer cells, and they may be involved in a spectrum of anti-tumor immune responses. Here, we review the current knowledge of the expression of SLAMF receptors in solid tumors and tumor-infiltrating immune cells and their association with patient outcomes. Furthermore, we discuss the therapeutic potential of targeting SLAMF receptors to improve outcomes of cancer therapy in solid tumors. We believe the research on SLAMF receptor-targeted strategies may enhance anti-cancer immunity in patients with solid tumors and improve clinical outcomes.
    Keywords:  SLAMF; cancer immunology; immunotherapy; signaling lymphocytic activation molecule family; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1297473
  31. Methods Mol Biol. 2024 ;2777 99-122
    Multicellular Tumoroids for Investigating Cancer Stem-Like Cells in the Heterogeneous Tumor Microenvironment.
    Kathleen M Burkhard, Geeta Mehta.
      Cancer stem-like cells (CSC) are a major contributing factor to chemoresistance, tumor recurrence, and poor survival outcomes in patients across cancer types. Signaling from non-tumor cells in the tumor microenvironment (TME) enriches for and supports CSC. This complex cell-cell signaling in the heterogeneous TME presents a challenge for patient survival; however, it also presents an opportunity to develop new targeted therapies that can inhibit survival of CSC. In this chapter, we report a multicellular tumoroid model which can be used to investigate the interactions between cancer cells and non-tumor cells in the TME to better understand the contribution of various cell types to cancer cell phenotypes, as well as the underlying mechanisms involved. The following methods allow for each cell type to be distinguished using FACS and studied individually. Gene expression can be analyzed for cancer cells, as well as the other non-tumor cells using qPCR following sorting. The response to chemotherapeutic agents and expression of stem markers can be determined for cancer cells using flow cytometry, excluding the other cell types to get an accurate view of the cancer cells. Furthermore, the viability of non-tumor cells can be analyzed as well to determine if there are cytotoxic effects of the drugs on non-tumor cells. Thus, the multicellular tumoroid model will reveal the interactions between the CSC and non-tumor cells in the heterogenous TME, resulting in discoveries in the fields of cancer biology, novel targeted therapies, and personalized drug screening for precision medicine.
    Keywords:  Alternately activated macrophages, AAM; Cancer stem-like cells, CSC; Carcinoma associated mesenchymal stem cells, CA-MSC; Carcinoma-associated fibroblasts, CAF; Heterogeneity; Immune microenvironment; Macrophages; Mesenchymal stem cells, MSC; Organoids; Spheroids; Tumor cells; Tumor microenvironment; Tumoroids
    DOI:  https://doi.org/10.1007/978-1-0716-3730-2_8
  32. Gastric Cancer. 2024 Mar 09.
    Specific lineage transition of tumor-associated macrophages elicits immune evasion of ascitic tumor cells in gastric cancer with peritoneal metastasis.
    Yilin Li, Lei Jiang, Yang Chen, Yanyan Li, Jiajia Yuan, Jialin Lu, Zizhen Zhang, Shengde Liu, Xujiao Feng, Jiaxin Xiong, Yan Jiang, Xiaotian Zhang, Jian Li, Lin Shen.
       BACKGROUND: Gastric cancer with peritoneal metastasis (PM-GC), recognized as one of the deadliest cancers. However, whether and how the tumor cell-extrinsic tumor microenvironment (TME) is involved in the therapeutic failure remains unknown. Thus, this study systematically assessed the immunosuppressive tumor microenvironment in ascites from patients with PM-GC, and its contribution to dissemination and immune evasion of ascites-disseminated tumor cells (aDTCs).
    METHODS: Sixty-three ascites and 43 peripheral blood (PB) samples from 51 patients with PM-GC were included in this study. aDTCs in ascites and circulating tumor cells (CTCs) in paired PB were immunophenotypically profiled. Using single-cell RNA transcriptional sequencing (scRNA-seq), crosstalk between aDTCs and the TME features of ascites was inspected. Further studies on the mechanism underlying aDTCs-immune cells crosstalk were performed on in vitro cultured aDTCs.
    RESULTS: Immune cells in ascites interact with aDTCs, prompting their immune evasion. Specifically, we found that the tumor-associated macrophages (TAMs) in ascites underwent a continuum lineage transition from cathepsinhigh (CTShigh) to complement 1qhigh (C1Qhigh) TAM. CTShigh TAM initially attracted the metastatic tumor cells to ascites, thereafter, transitioning terminally to C1Qhigh TAM to trigger overproliferation and immune escape of aDTCs. Mechanistically, we demonstrated that C1Qhigh TAMs significantly enhanced the expression of PD-L1 and NECTIN2 on aDTCs, which was driven by the activation of the C1q-mediated complement pathway.
    CONCLUSIONS: For the first time, we identified an immunosuppressive macrophage transition from CTShigh to C1Qhigh TAM in ascites from patients with PM-GC. This may contribute to developing potential TAM-targeted immunotherapies for PM-GC.
    Keywords:  Ascitic tumor; Gastric cancer; Immune evasion; Peritoneal metastasis; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s10120-024-01486-6
  33. Front Cell Infect Microbiol. 2024 ;14 1384645
    Editorial: New insights into the role of tumor microbial microenvironment in tumor immunotherapy.
    Peixin Dong, Xu Chen, Jianguo Tang, Wei Wang.
      
    Keywords:  microbial metabolites; microbiome; tumor immunotherapy; tumor microbial microenvironment; tumor viruses
    DOI:  https://doi.org/10.3389/fcimb.2024.1384645
  34. Cell Death Discov. 2024 Mar 14. 10(1): 140
    MCT4-driven CAF-mediated metabolic reprogramming in breast cancer microenvironment is a vulnerability targetable by miR-425-5p.
    Alessandra Affinito, Cristina Quintavalle, Rosario Vincenzo Chianese, Giuseppina Roscigno, Danilo Fiore, Valeria D'Argenio, Guglielmo Thomas, Alessia Savarese, Francesco Ingenito, Lorenza Cocca, Silvia Nuzzo, Maxim V Berezovski, Maria Patrizia Stoppelli, Gerolama Condorelli.
      Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.
    DOI:  https://doi.org/10.1038/s41420-024-01910-x
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