bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–08–25
eightteen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Role of tumor-associated macrophages in hepatocellular carcinoma: impact, mechanism, and therapy.
  2. Molecular understanding and clinical aspects of tumor-associated macrophages in the immunotherapy of renal cell carcinoma.
  3. Gynecological cancer tumor Microenvironment: Unveiling cellular complexity and therapeutic potential.
  4. Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight.
  5. TALEN-edited Allogeneic Inducible Dual CAR T-cells Enable Effective Targeting of Solid Tumors while Mitigating Off-Tumor Toxicity.
  6. Manganese-mediated potentiation of antitumor immune responses by enhancing KLRG1+ Macrophage function.
  7. Pediatric cancer-pathology and microenvironment influence: a perspective into osteosarcoma and non-osteogenic mesenchymal malignant neoplasms.
  8. A Bibliometric Analysis of Metabolic Reprogramming in the Tumor Microenvironment From 2003 to 2022.
  9. Hypoxia-Driven Changes in Tumor Microenvironment: Insights into Exosome-Mediated Cell Interactions.
  10. Jump-starting chimeric antigen receptor-T cells to go the extra mile with nanotechnology.
  11. Excessive lipid production shapes glioma tumor microenvironment.
  12. Dissecting the emerging role of cancer-associated adipocyte-derived cytokines in remodeling breast cancer progression.
  13. Targeting tumor microenvironment for non-small cell lung cancer immunotherapy.
  14. Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.
  15. The role of microRNAs in the gastric cancer tumor microenvironment.
  16. The current status and future of targeted-immune combination for hepatocellular carcinoma.
  17. TME-NET: an interpretable deep neural network for predicting pan-cancer immune checkpoint inhibitor responses.
  18. Strategies to overcome tumor microenvironment immunosuppressive effect on the functioning of CAR-T cells in high-grade glioma.
  1. Front Immunol. 2024 ;15 1429812
    Role of tumor-associated macrophages in hepatocellular carcinoma: impact, mechanism, and therapy.
    Yinqi Zhang, Guoyong Han, Jian Gu, Zhiqiang Chen, Jindao Wu.
      Hepatocellular carcinoma (HCC) is a highly frequent malignancy worldwide. The occurrence and progression of HCC is a complex process closely related to the polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). The polarization of TAMs is affected by a variety of signaling pathways and surrounding cells. Evidence has shown that TAMs play a crucial role in HCC, through its interaction with other immune cells in the TME. This review summarizes the origin and phenotypic polarization of TAMs, their potential impacts on HCC, and their mechanisms and potential targets for HCC immunotherapy.
    Keywords:  hepatocellular carcinoma; immunotherapy; treatment resistance; tumor angiogenesis; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2024.1429812
  2. J Exp Clin Cancer Res. 2024 Aug 22. 43(1): 242
    Molecular understanding and clinical aspects of tumor-associated macrophages in the immunotherapy of renal cell carcinoma.
    Han Liu, Zongwei Lv, Gong Zhang, Zhenhong Yan, Song Bai, Dan Dong, Kefeng Wang.
      Renal cell carcinoma (RCC) is one of the most common tumors that afflicts the urinary system, accounting for 90-95% of kidney cancer cases. Although its incidence has increased over the past decades, its pathogenesis is still unclear. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising more than 50% of the tumor volume. By interacting with cancer cells, TAMs can be polarized into two distinct phenotypes, M1-type and M2-type TAMs. In the TME, M2-type TAMs, which are known to promote tumorigenesis, are more abundant than M1-type TAMs, which are known to suppress tumor growth. This ratio of M1 to M2 TAMs can create an immunosuppressive environment that contributes to tumor cell progression and survival. This review focused on the role of TAMs in RCC, including their polarization, impacts on tumor proliferation, angiogenesis, invasion, migration, drug resistance, and immunosuppression. In addition, we discussed the potential of targeting TAMs for clinical therapy in RCC. A deeper understanding of the molecular biology of TAMs is essential for exploring innovative therapeutic strategies for the treatment of RCC.
    Keywords:  Immunotherapy; Renal cell carcinoma; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s13046-024-03164-y
  3. Biochem Pharmacol. 2024 Aug 17. pii: S0006-2952(24)00481-7. [Epub ahead of print]229 116498
    Gynecological cancer tumor Microenvironment: Unveiling cellular complexity and therapeutic potential.
    Pankaj Garg, Sravani K Ramisetty, Ayalur Raghu Subbalakshmi, B Madhu Krishna, Siddhika Pareek, Atish Mohanty, Prakash Kulkarni, David Horne, Ravi Salgia, Sharad S Singhal.
      Gynecological cancers, including ovarian, cervical, endometrial, and vulvar cancers, present significant challenges in diagnosis and treatment globally. The tumor microenvironment (TME) plays a pivotal role in cancer progression and therapy response, necessitating a deeper understanding of its composition and dynamics. This review offers a comprehensive overview of the gynecological cancer tumor microenvironment, emphasizing its cellular complexity and therapeutic potential. The diverse cellular components of the TME, including cancer cells, immune cells, stromal cells, and extracellular matrix elements, are explored, elucidating their interplay in shaping tumor behavior and treatment outcomes. Across various stages of cancer progression, the TME exerts profound effects on tumor heterogeneity, immune modulation, angiogenesis, and metabolic reprogramming. The urgency for novel therapeutic strategies is underscored by understanding immune evasion mechanisms within the TME. Emerging approaches such as immunotherapy, stromal-targeting therapies, anti-angiogenic agents, and metabolic inhibitors are discussed, offering promising avenues for improving patient outcomes. Interdisciplinary collaborations and translational research are emphasized, aiming to advance precision oncology and enhance therapeutic efficacy in gynecological cancers.
    Keywords:  Gynecological cancers; Immune evasion; Precision medicine; Therapeutic approaches; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bcp.2024.116498
  4. Cancer Cell Int. 2024 Aug 22. 24(1): 295
    Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight.
    Zhongshu Lin, Guanxiang Hua, Xiaojuan Hu.
      Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.
    DOI:  https://doi.org/10.1186/s12935-024-03481-4
  5. Mol Ther. 2024 Aug 20. pii: S1525-0016(24)00540-9. [Epub ahead of print]
    TALEN-edited Allogeneic Inducible Dual CAR T-cells Enable Effective Targeting of Solid Tumors while Mitigating Off-Tumor Toxicity.
    Sonal Dharani, Hana Cho, Jorge Postigo Fernandez, Alexandre Juillerat, Julien Valton, Philippe Duchateau, Laurent Poirot, Shipra Das.
      Adoptive cell therapy using chimeric antigen receptor (CAR) T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has been limited in solid tumors. One key factor for this are cancer-associated fibroblasts (CAFs), that modulate the tumor microenvironment (TME) to inhibit T cell infiltration and induce "T cell dysfunction". Additionally, the sparsity of tumor-specific antigens (TSA) and expression of CAR-directed tumor-associated antigens (TAA) on normal tissues often results in "on-target off-tumor" cytotoxicity, raising safety concerns. Using TALEN-mediated gene editing, we present here an innovative CAR-T cell engineering strategy to overcome these challenges. Our allogeneic "Smart CAR T-cells" are designed to express a constitutive CAR, targeting FAP+ CAFs in solid tumors. Additionally, a second CAR targeting a Tumor Associated Antigen (TAA) such as mesothelin is specifically integrated at a TCR signaling-inducible locus like PDCD1. FAPCAR-mediated CAF targeting induces expression of the mesothelin-CAR, establishing an IF/THEN-gated circuit sensitive to dual antigen sensing. Using this approach, we observe enhanced anti-tumor cytotoxicity, while limiting "on-target off-tumor" toxicity. Our study thus demonstrates TALEN-mediated gene editing capabilities for design of allogeneic IF/THEN-gated Dual CAR T-cells which efficiently target immunotherapy-recalcitrant solid tumors while mitigating potential safety risks, encouraging clinical development of this strategy.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.08.018
  6. Int Immunopharmacol. 2024 Aug 16. pii: S1567-5769(24)01472-3. [Epub ahead of print]141 112951
    Manganese-mediated potentiation of antitumor immune responses by enhancing KLRG1+ Macrophage function.
    Liyan Ge, Hui Guo, Wei Zhou, Weifeng Shi, Jiawei Yue, Yumin Wu.
      Manganese (Mn) play a crucial role in various biological processes in the body. Studies have primarily focused on their ability to enhance immune cell function and activation against tumors, particularly in dendritic cells (DCs), macrophages, and T cells. Tumor-associated macrophages (TAMs) are often the most abundant immune cell population present in the tumor microenvironment (TME). Thus, it would be valuable to investigate the mechanism by which Mn2+ regulates TAMs' involvement in anti-tumor immunity, as it be crucial for advancing our understanding of cancer biology and developing new treatments for cancer. Here, in the present study we discovered that Mn2+ treatment led to a significant increase in KLRG1+ macrophages (KLRG1+ Mφ) in tumor tissues, and most of these cells exhibited an M1 phenotype. Knocking down KLRG1 in macrophages not only impaired their ability to induce downstream anti-tumor immunity of adaptive immune cells, but also impaired their direct cytotoxicity against tumor cells. Moreover, the changes in the polarization phenotype of KLRG1+ macrophages further lead to T cell proliferation and the polarization of CD4+ T cells towards a Th1 phenotype, thereby establishing a foundation for the antitumor immune response. Our study expands the understanding of the anti-tumor mechanism of Mn2+ and demonstrates, for the first time, that Mn2+ can regulate the function of KLRG1+ Mφ to participate in anti-tumor activities. These findings suggest that KLRG1 may represent a promising target for developing new tumor therapy.
    Keywords:  Antitumor; Immune responses; KLRG1; Macrophage; Manganese
    DOI:  https://doi.org/10.1016/j.intimp.2024.112951
  7. Discov Oncol. 2024 Aug 18. 15(1): 358
    Pediatric cancer-pathology and microenvironment influence: a perspective into osteosarcoma and non-osteogenic mesenchymal malignant neoplasms.
    Consolato M Sergi.
      Pediatric cancer remains the leading cause of disease-related death among children aged 1-14 years. A few risk factors have been conclusively identified, including exposure to pesticides, high-dose radiation, and specific genetic syndromes, but the etiology underlying most events remains unknown. The tumor microenvironment (TME) includes stromal cells, vasculature, fibroblasts, adipocytes, and different subsets of immunological cells. TME plays a crucial role in carcinogenesis, cancer formation, progression, dissemination, and resistance to therapy. Moreover, autophagy seems to be a vital regulator of the TME and controls tumor immunity. Autophagy is an evolutionarily conserved intracellular process. It enables the degradation and recycling of long-lived large molecules or damaged organelles using the lysosomal-mediated pathway. The multifaceted role of autophagy in the complicated neoplastic TME may depend on a specific context. Autophagy may function as a tumor-suppressive mechanism during early tumorigenesis by eliminating unhealthy intracellular components and proteins, regulating antigen presentation to and by immune cells, and supporting anti-cancer immune response. On the other hand, dysregulation of autophagy may contribute to tumor progression by promoting genome damage and instability. This perspective provides an assortment of regulatory substances that influence the features of the TME and the metastasis process. Mesenchymal cells in bone and soft-tissue sarcomas and their signaling pathways play a more critical role than epithelial cells in childhood and youth. The investigation of the TME in pediatric malignancies remains uncharted primarily, and this unique collection may help to include novel advances in this setting.
    Keywords:  Epithelial-to-mesenchymal transition; Mesenchymal-to-epithelial transition; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-024-01240-5
  8. Cancer Rep (Hoboken). 2024 Aug;7(8): e2146
    A Bibliometric Analysis of Metabolic Reprogramming in the Tumor Microenvironment From 2003 to 2022.
    Yupeng Xi, Rui Liu, Xing Zhang, Qiujun Guo, Xiwen Zhang, Zizhen Yang, Honggang Zheng, Qingqiao Song, Baojin Hua.
       BACKGROUND: Despite considerable progress in cancer immunotherapy, it is not available for many patients. Resistance to immune checkpoint blockers arises from the intricate interactions between cancer and its microenvironment. Metabolic reprogramming in tumor and immune cells in the tumor microenvironment (TME) influences anti-tumor immune responses by remodeling the immune microenvironment. Metabolic reprogramming has emerged as an important hallmark of tumorigenesis. However, few studies have focused on the TME and metabolic reprogramming. Therefore, we aimed to explore the current research status and popular topics in TME-related metabolic reprogramming over a 20 years using a bibliometric approach.
    METHODS: Studies focusing on metabolic reprogramming and TME were searched using the Web of Science Core Collection database. Bibliometric and visual analyses of the articles and reviews were performed using Bibliometrix, VOSviewer, and CiteSpace.
    RESULTS: In total, 4726 articles published between 2003 and 2022 were selected. The number of publications and citations has increased annually. Cooperation network analysis indicated that the United States holds the foremost position in metabolic reprogramming and TME research with the highest volume of publications and citations, thus exerting the greatest influence. Among these institutions, Fudan University displayed the highest level of productivity. Frontiers in Immunology showed the highest degree of productivity in this field. Ho Ping-Chih made the most article contributions, and Pearce Edward J. was the most co-cited author. Four clusters were obtained after a cluster analysis of the authors' keywords: TME, metabolic reprogramming, immunometabolism, and immunity. Immunometabolism, glycolysis, immune cells, and tumor-associated macrophages are relatively recent keywords that have attracted increasing attention.
    CONCLUSIONS: A comprehensive landscape of advancements in metabolic reprogramming and the TME was evaluated, which provided crucial information for scholars to further advance this promising field. Further research should explore new topics related to immunometabolism in the TME using a transdisciplinary approach.
    Keywords:  bibliometric analysis; immunotherapy; metabolic reprogramming; tumor microenvironment; tumor‐infiltrating immune cells
    DOI:  https://doi.org/10.1002/cnr2.2146
  9. Int J Nanomedicine. 2024 ;19 8211-8236
    Hypoxia-Driven Changes in Tumor Microenvironment: Insights into Exosome-Mediated Cell Interactions.
    Churan Wang, Shun Xu, Xiao Yang.
      Hypoxia, as a prominent feature of the tumor microenvironment, has a profound impact on the multicomponent changes within this environment. Under hypoxic conditions, the malignant phenotype of tumor cells, the variety of cell types within the tumor microenvironment, as well as intercellular communication and material exchange, undergo complex alterations. These changes provide significant prospects for exploring the mechanisms of tumor development under different microenvironmental conditions and for devising therapeutic strategies. Exosomes secreted by tumor cells and stromal cells are integral components of the tumor microenvironment, serving as crucial mediators of intercellular communication and material exchange, and have consequently garnered increasing attention from researchers. This review focuses on the mechanisms by which hypoxic conditions promote the release of exosomes by tumor cells and alter their encapsulated contents. It also examines the effects of exosomes derived from tumor cells, immune cells, and other cell types under hypoxic conditions on the tumor microenvironment. Additionally, we summarize current research progress on the potential clinical applications of exosomes under hypoxic conditions and propose future research directions in this field.
    Keywords:  exosomes; hypoxia; tumor microenvironment; vesicles
    DOI:  https://doi.org/10.2147/IJN.S479533
  10. Curr Opin Biotechnol. 2024 Aug 20. pii: S0958-1669(24)00115-0. [Epub ahead of print]89 103179
    Jump-starting chimeric antigen receptor-T cells to go the extra mile with nanotechnology.
    Neil C Chada, John T Wilson.
      Despite success in treating hematologic malignancies, chimeric antigen receptor-T cell (CAR-T) therapy still faces multiple challenges that have halted progress, especially against solid tumors. Recent advances in nanoscale engineeirng provide several avenues for overcoming these challenges, including more efficienct programming of CAR-Ts ex vivo, promoting immune responsiveness in the tumor microenvironment (TME) in vivo, and boosting CAR-T function in situ. Here, we summarize recent innovations that leverage nanotechnology to directly address the major obstacles that impede CAR-T therapy from reaching its full potential across various cancer types. We conclude with a commentary on the state of the field and how nanotechnology can shape the future of CAR-T and adoptive cell therapy in immuno-oncology.
    DOI:  https://doi.org/10.1016/j.copbio.2024.103179
  11. Ultrastruct Pathol. 2024 Aug 19. 1-11
    Excessive lipid production shapes glioma tumor microenvironment.
    Haitham H Maraqah, John Paul Aboubechara, Mones S Abu-Asab, Han Sung Lee, Orwa Aboud.
      Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.
    Keywords:  Astrocytoma; glioblastoma; glycolysis; immune evasion; lipid accumulation; mitochondrial dysfunction; oxidative phosphorylation; therapeutic strategies; tumor microenvironment; ultrastructural analysis
    DOI:  https://doi.org/10.1080/01913123.2024.2392728
  12. Heliyon. 2024 Aug 15. 10(15): e35200
    Dissecting the emerging role of cancer-associated adipocyte-derived cytokines in remodeling breast cancer progression.
    Zihui Yang, Hong Zeng, Jia Li, Ning Zeng, Qi Zhang, Kai Hou, Jie Li, Jing Yu, Yiping Wu.
      Breast cancer has been reported to transcend lung cancer as the most commonly diagnosed cancer in women all over the world. Adipocytes, serving as energy storage and endocrine cells, are the major stromal cells in the breast. Cancer-associated adipocytes (CAAs) are adjacent and dedifferentiated adipocytes located at the invasive front of human breast tumors. Adipocytes can transform into CAA phenotype with morphological and biological changes under the remodeling of breast cancer cells. CAAs play an essential role in breast cancer progression, including remodeling the tumor microenvironment (TME), regulating immunity, and interacting with breast cancer cells. CAAs possess peculiar secretomes and are accordingly capable to promote proliferation, invasiveness, angiogenesis, metastasis, immune escape, and drug resistance of breast cancer cells. There is a complex and coordinated crosstalk among CAAs, immune cells, and breast cancer cells. CAAs can release a variety of cytokines, including IL-6, IL-8, IL-1β, CCL5, CCL2, VEGF, G-CSF, IGF-1, and IGFBP, thereby promoting immune cell recruitment and macrophage polarization, and ultimately stimulating malignant behaviors in breast cancer cells. Here, we aim to provide a comprehensive description of CAA-derived cytokines, including their impact on cancer cell behaviors, immune regulation, breast cancer diagnosis, and treatment. A deeper understanding of CAA performance and interactions with specific TME cell populations will provide better strategies for cancer treatment and breast reconstruction after mastectomy.
    Keywords:  Breast cancer; Cancer-associated adipocytes; Cytokines; Immune regulation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e35200
  13. Chin Med J Pulm Crit Care Med. 2023 Mar;1(1): 18-29
    Targeting tumor microenvironment for non-small cell lung cancer immunotherapy.
    Lei Wang, Qingzhu Jia, Qian Chu, Bo Zhu.
      The tumor microenvironment (TME) is composed of different cellular and non-cellular elements. Constant interactions between tumor cells and the TME are responsible for tumor initiation, tumor progression, and responses to therapies. Immune cells in the TME can be classified into two broad categories, namely adaptive and innate immunity. Targeting these immune cells has attracted substantial research and clinical interest. Current research focuses on identifying key molecular players and developing targeted therapies. These approaches may offer more efficient ways of treating different cancers. In this review, we explore the heterogeneity of the TME in non-small cell lung cancer, summarize progress made in targeting the TME in preclinical and clinical studies, discuss the potential predictive value of the TME in immunotherapy, and highlight the promising effects of bispecific antibodies in the era of immunotherapy.
    Keywords:  Adaptive immune cell; Biomarker; Bispecific antibody; Immunotherapy; Innate immune cell; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.pccm.2022.11.001
  14. Mol Ther. 2024 Aug 20. pii: S1525-0016(24)00541-0. [Epub ahead of print]
    Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.
    Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong.
      Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates the CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor-erythroid 2-related-2 (Nrf2) is ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR)-T cells under ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using adoptive transfer model of antigen-specific CD8+ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.08.019
  15. Mol Cancer. 2024 Aug 20. 23(1): 170
    The role of microRNAs in the gastric cancer tumor microenvironment.
    Xianzhe Yu, Yin Zhang, Fengming Luo, Qinghua Zhou, Lingling Zhu.
       BACKGROUND: Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME.
    MAIN TEXT: A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC.
    CONCLUSIONS: miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
    Keywords:  Angiogenesis; Exosomes; Gastric cancer; Immune cells; MicroRNA; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-024-02084-x
  16. Front Immunol. 2024 ;15 1418965
    The current status and future of targeted-immune combination for hepatocellular carcinoma.
    Liyuan Hao, Shenghao Li, Fanghang Ye, Hengyi Wang, Yuxin Zhong, Xiaoyi Zhang, Xiaoyu Hu, Xiaopeng Huang.
      Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy".
    Keywords:  CTLA-4; HCC; ICIS; anti-PD-1; anti-PD-L1; targeted-immune combination
    DOI:  https://doi.org/10.3389/fimmu.2024.1418965
  17. Brief Bioinform. 2024 Jul 25. pii: bbae410. [Epub ahead of print]25(5):
    TME-NET: an interpretable deep neural network for predicting pan-cancer immune checkpoint inhibitor responses.
    Xiaobao Ding, Lin Zhang, Ming Fan, Lihua Li.
      Immunotherapy with immune checkpoint inhibitors (ICIs) is increasingly used to treat various tumor types. Determining patient responses to ICIs presents a significant clinical challenge. Although components of the tumor microenvironment (TME) are used to predict patient outcomes, comprehensive assessments of the TME are frequently overlooked. Using a top-down approach, the TME was divided into five layers-outcome, immune role, cell, cellular component, and gene. Using this structure, a neural network called TME-NET was developed to predict responses to ICIs. Model parameter weights and cell ablation studies were used to investigate the influence of TME components. The model was developed and evaluated using a pan-cancer cohort of 948 patients across four cancer types, with Area Under the Curve (AUC) and accuracy as performance metrics. Results show that TME-NET surpasses established models such as support vector machine and k-nearest neighbors in AUC and accuracy. Visualization of model parameter weights showed that at the cellular layer, Th1 cells enhance immune responses, whereas myeloid-derived suppressor cells and M2 macrophages show strong immunosuppressive effects. Cell ablation studies further confirmed the impact of these cells. At the gene layer, the transcription factors STAT4 in Th1 cells and IRF4 in M2 macrophages significantly affect TME dynamics. Additionally, the cytokine-encoding genes IFNG from Th1 cells and ARG1 from M2 macrophages are crucial for modulating immune responses within the TME. Survival data from immunotherapy cohorts confirmed the prognostic ability of these markers, with p-values <0.01. In summary, TME-NET performs well in predicting immunotherapy responses and offers interpretable insights into the immunotherapy process. It can be customized at https://immbal.shinyapps.io/TME-NET.
    Keywords:  deep learning; immune checkpoint inhibitor; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1093/bib/bbae410
  18. Ther Adv Med Oncol. 2024 ;16 17588359241266140
    Strategies to overcome tumor microenvironment immunosuppressive effect on the functioning of CAR-T cells in high-grade glioma.
    Julia Zarychta, Adrian Kowalczyk, Anna Marszołek, Joanna Zawitkowska, Monika Lejman.
      Despite significant progress in the treatment of some types of cancer, high-grade gliomas (HGGs) remain a significant clinical problem. In the case of glioblastoma (GBM), the most common solid tumor of the central nervous system in adults, the average survival time from diagnosis is only 15-18 months, despite the use of intensive multimodal therapy. Chimeric antigen receptor (CAR)-expressing T cells, which have already been approved by the Food and Drug Administration for use in the treatment of certain hematologic malignancies, are a new, promising therapeutic option. However, the efficacy of CAR-T cells in solid tumors is lower due to the immunosuppressive tumor microenvironment (TME). Reprogramming the immunosuppressive TME toward a pro-inflammatory phenotype therefore seems particularly important because it may allow for increasing the effectiveness of CAR-T cells in the therapy of solid tumors. The following literature review aims to present the results of preclinical studies showing the possibilities of improving the efficacy of CAR-T in the TME of GBM by reprogramming the TME toward a pro-inflammatory phenotype. It may be achievable thanks to the use of CAR-T in a synergistic therapy in combination with oncolytic viruses, radiotherapy, or epigenetic inhibitors, as well as by supporting CAR-T cells crossing of the blood-brain barrier, normalizing impaired angiogenesis in the TME, improving CAR-T effector functions by cytokine signaling or by blocking/knocking out T-cell inhibitors, and modulating the microRNA expression. The use of CAR-T cells modified in this way in synergistic therapy could lead to the longer survival of patients with HGG by inducing an endogenous anti-tumor response.
    Keywords:  chimeric antigen receptor; glioblastoma; immunosuppressive tumor microenvironment
    DOI:  https://doi.org/10.1177/17588359241266140
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