bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–07–21
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. T cell dysfunction and therapeutic intervention in cancer.
  2. Roles of Menin in T cell differentiation and function: Current knowledge and perspectives.
  3. Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism.
  4. Metabolic reprogramming and dysregulated IL-17 production impairs CD4 T cell function post sepsis.
  5. CD5 deletion enhances the antitumor activity of adoptive T cell therapies.
  6. The role of CD8+ T-cells in colorectal cancer immunotherapy.
  7. Immune surveillance of senescence: potential application to age-related diseases.
  8. Regulation of gut microbiota on immune cell ferroptosis: A novel insight for immunotherapy against tumor.
  1. Nat Immunol. 2024 Jul 18.
    T cell dysfunction and therapeutic intervention in cancer.
    Caitlin C Zebley, Dietmar Zehn, Stephen Gottshalk, Hongbo Chi.
      Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8+ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer.
    DOI:  https://doi.org/10.1038/s41590-024-01896-9
  2. Immunology. 2024 Jul 16.
    Roles of Menin in T cell differentiation and function: Current knowledge and perspectives.
    Pingping Zhou, Weiru Liu, Jian Ma.
      The commitment to specific T lymphocytes (T cell) lineages is governed by distinct transcription factors, whose expression is modulated through epigenetic mechanisms. Unravelling these epigenetic mechanisms that regulate T cell differentiation and function holds significant importance for understanding T cells. Menin, a multifunctional scaffolding protein, is implicated in various cellular processes, such as cell proliferation, cell cycle control, DNA repair and transcriptional regulation, primarily through epigenetic mechanisms. Existing research indicates Menin's impact on T cell differentiation and function, while a comprehensive and systematic review is currently lacking to consolidate these findings. In the current review, we have highlighted recent studies on the role of Menin in T cell differentiation and function, focusing mainly on its impact on the memory Th2 maintenance, Th17 differentiation and maintenance, CD4+ T cell senescence, and effector CD8+ T cell survival. Considering Menin's crucial function in maintaining effector T cell function, the potential of inhibiting Menin activity in mitigating inflammatory diseases associated with excessive T cell activation has also been emphasised.
    Keywords:  Menin; T lymphocytes; differentiation; epigenetic mechanism; function
    DOI:  https://doi.org/10.1111/imm.13837
  3. bioRxiv. 2024 Jul 11. pii: 2024.07.08.602554. [Epub ahead of print]
    Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism.
    KayLee K Steiner, Arissa C Young, Andrew R Patterson, Erin Q Jennings, Channing Chi, Zaid Hatem, Darren Heintzman, Ayaka Sugiura, Emily N Arner, Allison E Sewell, Matthew Z Madden, Richmond Okparaugo, Emilia V Fallman, Katherine Gibson-Corley, Kelsey Voss, Denis Mogilenko, Jeffrey Rathmell.
      Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.
    DOI:  https://doi.org/10.1101/2024.07.08.602554
  4. iScience. 2024 Jul 19. 27(7): 110114
    Metabolic reprogramming and dysregulated IL-17 production impairs CD4 T cell function post sepsis.
    Patricia A Assis, Ronald M Allen, Matthew A Schaller, Steven L Kunkel, Jennifer R Bermick.
      Sepsis survivors are at high risk for infection-related rehospitalization and mortality for years following the resolution of the acute septic event. These infection-causing microorganisms generally do not cause disease in immunocompetent hosts, suggesting that the post-septic immune response is compromised. Given the importance of CD4 T cells in the development of long-lasting protective immunity, we analyzed their post-septic function. Here we showed that sepsis induced chronic increased and non-specific production of IL-17 by CD4 T cells, resulting in the inability to mount an effective immune response to a secondary pneumonia challenge. Altered cell function was associated with metabolic reprogramming, characterized by mitochondrial dysfunction and increased glycolysis. This metabolic reprogramming began during the acute septic event and persisted long after sepsis had resolved. Our findings reveal cell metabolism as a potential therapeutic target. Given the critical role of cell metabolism in the physiological and pathophysiological processes of immune cells, these findings reveal a potential new therapeutic target to help mitigate sepsis survivors' susceptibility to secondary infections.
    Keywords:  Components of the immune system; Immunology; Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.110114
  5. Sci Immunol. 2024 Jul 19. 9(97): eadn6509
    CD5 deletion enhances the antitumor activity of adoptive T cell therapies.
    Ruchi P Patel, Guido Ghilardi, Yunlin Zhang, Yi-Hao Chiang, Wei Xie, Puneeth Guruprasad, Ki Hyun Kim, Inkook Chun, Mathew G Angelos, Raymone Pajarillo, Seok Jae Hong, Yong Gu Lee, Olga Shestova, Carolyn Shaw, Ivan Cohen, Aasha Gupta, Trang Vu, Dean Qian, Steven Yang, Aditya Nimmagadda, Adam E Snook, Nicholas Siciliano, Antonia Rotolo, Arati Inamdar, Jaryse Harris, Ositadimma Ugwuanyi, Michael Wang, Alberto Carturan, Luca Paruzzo, Linhui Chen, Hatcher J Ballard, Tatiana Blanchard, Chong Xu, Mohamed Abdel-Mohsen, Khatuna Gabunia, Maria Wysocka, Gerald P Linette, Beatriz Carreno, David M Barrett, David T Teachey, Avery D Posey, Daniel J Powell, C Tor Sauter, Stefano Pileri, Vinodh Pillai, John Scholler, Alain H Rook, Stephen J Schuster, Stefan K Barta, Patrizia Porazzi, Marco Ruella.
      Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
    DOI:  https://doi.org/10.1126/sciimmunol.adn6509
  6. Heliyon. 2024 Jun 30. 10(12): e33144
    The role of CD8+ T-cells in colorectal cancer immunotherapy.
    Tao He, Chencheng Hu, Shichao Li, Yao Fan, Fei Xie, Xin Sun, Qingfeng Jiang, Weidong Chen, Yingtian Jia, Wusheng Li.
      Immunotherapy has been an advanced and effective approach to treating various types of solid tumors in recent years, and the most successful strategy is immune checkpoint inhibitors (ICIs), which have shown beneficial effects in patients with colorectal cancer (CRC). Drug resistance to ICIs is usually associated with CD8+ T-cells targeting tumor antigens; thus, CD8+ T-cells play an important role in immunotherapy. Unfortunately, Under continuous antigen stimulation, tumor microenvironment(TME), hypoxia and other problems it leads to insufficient infiltration of CD8+ T-cells, low efficacy and mechanism exhaustion, which have become obstacles to immunotherapy. Thus, this article describes the relationship between CRC and the immune system, focuses on the process of CD8+ T-cells production, activation, transport, killing, and exhaustion, and expounds on related mechanisms leading to CD8+ T-cells exhaustion. Finally, this article summarizes the latest strategies and methods in recent years, focusing on improving the infiltration, efficacy, and exhaustion of CD8+ T-cells, which may help to overcome the barriers to immunotherapy.
    Keywords:  CD8+ T-cells; Colorectal cancer; Immunotherapy; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e33144
  7. Trends Cell Biol. 2024 Jul 17. pii: S0962-8924(24)00121-1. [Epub ahead of print]
    Immune surveillance of senescence: potential application to age-related diseases.
    Teh-Wei Wang, Makoto Nakanishi.
      Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.
    Keywords:  immune checkpoint blockade; immune clearance; senescence
    DOI:  https://doi.org/10.1016/j.tcb.2024.06.007
  8. Cancer Lett. 2024 Jul 16. pii: S0304-3835(24)00510-X. [Epub ahead of print] 217115
    Regulation of gut microbiota on immune cell ferroptosis: A novel insight for immunotherapy against tumor.
    Ruobing Liu, Juanjuan Wang, Yuqing Liu, Yunhuan Gao, Rongcun Yang.
      Gut microbiota contributes to the homeostasis of immune system and is related to various diseases such as tumorigenesis. Ferroptosis, a new type of cell death, is also involved in the disease pathogenesis. Recent studies have found the correlations of gut microbiota mediated ferroptosis and immune cell death. Gut microbiota derived immunosuppressive metabolites, which can promote differentiation and function of immune cells, tend to inhibit ferroptosis through their receptors, whereas inflammatory metabolites from gut microbiota also affect the differentiation and function of immune cells and their ferroptosis. Thus, it is possible for gut microbiota to regulate immune cell ferroptosis. Indeed, gut microbiota metabolite receptor aryl hydrocarbon receptor (AhR) can affect ferroptosis of intestinal intraepithelial lymphocytes, leading to disease pathogenesis. Since immune cell ferroptosis in tumor microenvironment (TME) affects the occurrence and development of tumor, the modulation of gut microbiota in these cell ferroptosis might influence on the tumorigenesis, and also immunotherapy against tumors. Here we will summarize the recent advance of ferroptosis mediated by gut microbiota metabolites, which potentially acts as regulator(s) on immune cells in TME for therapy against tumor.
    DOI:  https://doi.org/10.1016/j.canlet.2024.217115
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