bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–01–28
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Melatonin: a modulator in metabolic rewiring in T-cell malignancies.
  2. Inosine induces stemness features in CAR-T cells and enhances potency.
  3. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
  4. BATF-mediated regulation of exhausted CD8+ T-cell responses and potential implications for chimeric antigen receptor-T therapy.
  5. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
  6. p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation.
  7. Regulation of IL-10 expression and function by JAK-STAT in CD8+ T cells.
  8. LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy.
  9. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
  10. Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
  11. Reduced mitochondrial respiration in peripheral T cells after paediatric heamatopoietic stem cell transplantation.
  12. Take my breath away-mitochondrial dysfunction drives CD8+ T cell exhaustion.
  13. Astragalus polysaccharide ameliorates CD8+ T cell dysfunction through STAT3/Gal-3/LAG3 pathway in inflammation-induced colorectal cancer.
  1. Front Oncol. 2023 ;13 1248339
    Melatonin: a modulator in metabolic rewiring in T-cell malignancies.
    Seema Rai, Gunja Roy, Younis Ahmad Hajam.
      Melatonin, (N-acetyl-5-methoxytryptamine) an indoleamine exerts multifaced effects and regulates numerous cellular pathways and molecular targets associated with circadian rhythm, immune modulation, and seasonal reproduction including metabolic rewiring during T cell malignancy. T-cell malignancies encompass a group of hematological cancers characterized by the uncontrolled growth and proliferation of malignant T-cells. These cancer cells exhibit a distinct metabolic adaptation, a hallmark of cancer in general, as they rewire their metabolic pathways to meet the heightened energy requirements and biosynthesis necessary for malignancies is the Warburg effect, characterized by a shift towards glycolysis, even when oxygen is available. In addition, T-cell malignancies cause metabolic shift by inhibiting the enzyme pyruvate Dehydrogenase Kinase (PDK) which in turn results in increased acetyl CoA enzyme production and cellular glycolytic activity. Further, melatonin plays a modulatory role in the expression of essential transporters (Glut1, Glut2) responsible for nutrient uptake and metabolic rewiring, such as glucose and amino acid transporters in T-cells. This modulation significantly impacts the metabolic profile of T-cells, consequently affecting their differentiation. Furthermore, melatonin has been found to regulate the expression of critical signaling molecules involved in T-cell activations, such as CD38, and CD69. These molecules are integral to T-cell adhesion, signaling, and activation. This review aims to provide insights into the mechanism of melatonin's anticancer properties concerning metabolic rewiring during T-cell malignancy. The present review encompasses the involvement of oncogenic factors, the tumor microenvironment and metabolic alteration, hallmarks, metabolic reprogramming, and the anti-oncogenic/oncostatic impact of melatonin on various cancer cells.
    Keywords:  T-cell exhaustion; T-cell malignancy; cancer; melatonin; metabolic rewiring; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1248339
  2. Cancer Cell. 2024 Jan 17. pii: S1535-6108(24)00008-4. [Epub ahead of print]
    Inosine induces stemness features in CAR-T cells and enhances potency.
    Dorota D Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A Freitas, Yiyun Chen, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Vimal Keerthi, Amaury Leruste, Malek Bashti, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L Davis, Ansuman T Satpathy, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
    DOI:  https://doi.org/10.1016/j.ccell.2024.01.002
  3. Nat Aging. 2024 Jan 24.
    Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
    Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe.
      Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.
    DOI:  https://doi.org/10.1038/s43587-023-00560-5
  4. Immunotherapy. 2024 Jan 24.
    BATF-mediated regulation of exhausted CD8+ T-cell responses and potential implications for chimeric antigen receptor-T therapy.
    Chao Sun, Dan Li, Zhengxin Wang.
      Chimeric antigen receptor (CAR) T-cell therapy for malignant tumors has reached a crucial stage, with recent studies underscoring the role of T-cell exhaustion in determining the efficacy of CAR-T therapy. This trailblazing discovery has opened new avenues to augment the potency of CAR-T therapy. Basic leucine zipper ATF-like transcription factor (BATF) is indispensable in alleviating T-cell exhaustion and is pivotal in the early stages of CD8+ T-cell differentiation. In cooperation with other transcription factors, it plays a key role in the differentiation and maturation processes of exhausted T cells. A deeper comprehension of BATF's mechanisms in T-cell biology may yield novel insights into amplifying the efficacy of CAR-T therapy.
    Keywords:  BATF; CD8+ T-cell differentiation; T-cell exhaustion; T-cell therapy; amplifying CAR-T efficacy; chimeric antigen receptor; efficacy; malignant tumors; potency; transcription factor
    DOI:  https://doi.org/10.2217/imt-2023-0170
  5. Nat Aging. 2024 Jan 24.
    TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
    Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang.
      Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1-cGAS interaction is a relevant target for selectively suppressing inflammaging.
    DOI:  https://doi.org/10.1038/s43587-023-00564-1
  6. J Clin Invest. 2024 Jan 25. pii: e172760. [Epub ahead of print]
    p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation.
    Hidetoshi Tsuda, Karen S Keslar, William M Baldwin Iii, Peter S Heeger, Anna Valujskikh, Robert L Fairchild.
      Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses antigen-reactive naïve and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here we dissected heterologous donor-reactive memory CD8 T cell proliferation and their effector functions following infiltration into heart allografts having low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions requires p40 homodimer-induced IL-15 transpresentation by graft dendritic cells, but expression of effector functions mediating acute allograft injury occurs only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8 T cells are distinct from donor antigen-primed memory CD8 T cells during early activation in allografts and at graft rejection. Overall, the results insights into mechanisms driving heterologous effector memory CD8 T cell proliferation and the separation between proliferation and effector function, that is dependent on the intensity of inflammation within the tissue microenvironment.
    Keywords:  Adaptive immunity; Innate immunity; Organ transplantation; Transplantation
    DOI:  https://doi.org/10.1172/JCI172760
  7. Int Immunopharmacol. 2024 Jan 19. pii: S1567-5769(24)00081-X. [Epub ahead of print]128 111563
    Regulation of IL-10 expression and function by JAK-STAT in CD8+ T cells.
    Yu Pei, Xiuping Cui, Yu Wang.
      IL-10 is a pleiotropic cytokine that plays a significant role in antiviral and antitumor immunity. Potent CD8+ T cells express IL-10 after stimulation by strong TCR signaling, which promotes the killing effect of CD8+ T cells. However, the regulation of IL-10 expression in CD8+ T cells and its signaling pathway to enhance CD8+ T cell function are largely unknown. In this study, we investigated the JAK-STAT signaling molecules that regulate IL-10 expression in CD8+ T cells and the JAK-STAT signaling pathway that IL-10 enhances the function of CD8+ T cells through its receptor, using small molecule inhibitors and CRISPR-Cas9 gene editing. Our findings provide new insights and a theoretical basis for the immunotherapy of tumors.
    DOI:  https://doi.org/10.1016/j.intimp.2024.111563
  8. J Immunother Cancer. 2024 Jan 25. pii: e008367. [Epub ahead of print]12(1):
    LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy.
    Lingjuan Sun, Zhibo Ma, Xiangli Zhao, Xiaosheng Tan, Yuhao Tu, Jingzeng Wang, Li Chen, Zhishui Chen, Gang Chen, Peixiang Lan.
       BACKGROUND: Tumor-infiltrating T cells enter an exhausted or dysfunctional state, which limits antitumor immunity. Among exhausted T cells, a subset of cells with features of progenitor or stem-like cells has been identified as TCF1+ CD8+ T cells that respond to immunotherapy. In contrast to the finding that TCF1 controls epigenetic and transcriptional reprogramming in tumor-infiltrating stem-like T cells, little is known about the regulation of TCF1. Emerging data show that elevated body mass index is associated with outcomes of immunotherapy. However, the mechanism has not been clarified.
    METHODS: We investigated the proliferation of splenic lymphocytes or CD8+ T cells induced by CD3/CD28 stimulation in vitro. We evaluated the effects of low-density lipoprotein (LDL) and LRP11 inhibitors, as well as MAPK13 inhibitors. Additionally, we used shRNA technology to validate the roles of LRP11 and MAPK13. In an in vivo setting, we employed male C57BL/6J injected with B16 cells or MC38 cells to build a tumor model to assess the effects of LDL and LRP11 inhibitors, LRP11 activators, MAPK13 inhibitors on tumor growth. Flow cytometry was used to measure cell proportions and activation status. Molecular interactions and TCF1 status were examined using Western blotting. Moreover, we employed RNA sequencing to investigate the effects of LDL stimulation and MAPK13 inhibition in CD8+ T cells.
    RESULTS: By using a tumor-bearing mouse model, we found that LDL-induced tumor-infiltrating TCF1+PD1+CD8+ T cells. Using a cell-based chimeric receptor screening system, we showed that LRP11 interacted with LDL and activated TCF1. LRP11 activation enhanced TCF1+PD1+CD8+ T-cell-mediated antitumor immunity, consistent with LRP11 blocking impaired T-cell function. Mechanistically, LRP11 activation induces MAPK13 activation. Then, MAPK13 phosphorylates TCF1, leading to increase of stem-like T cells.
    CONCLUSIONS: LRP11-MAPK13-TCF1 enhanced antitumor immunity and induced tumor-infiltrating stem-like T cells.
    Keywords:  Drug Therapy, Combination; Immune Checkpoint Inhibitors; Immunotherapy; Lymphocytes, Tumor-Infiltrating
    DOI:  https://doi.org/10.1136/jitc-2023-008367
  9. Nat Immunol. 2024 Jan 23.
    Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
    Jingwei Ma, Liang Tang, Yaoyao Tan, Jingxuan Xiao, Keke Wei, Xin Zhang, Yuan Ma, Shuai Tong, Jie Chen, Nannan Zhou, Li Yang, Zhang Lei, Yonggang Li, Jiadi Lv, Junwei Liu, Huafeng Zhang, Ke Tang, Yi Zhang, Bo Huang.
      The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-023-01738-0
  10. Cell Death Discov. 2024 Jan 20. 10(1): 39
    Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
    Sheng Zhang, Kebing Lv, Zhen Liu, Ran Zhao, Fei Li.
      Metabolic competition between tumour cells and immune cells for limited nutrients is an important feature of the tumour microenvironment (TME) and is closely related to the outcome of tumour immune escape. A large number of studies have proven that tumour cells need metabolic reprogramming to cope with acidification and hypoxia in the TME while increasing energy uptake to support their survival. Among them, synthesis, oxidation and uptake of fatty acids (FAs) in the TME are important manifestations of lipid metabolic adaptation. Although different immune cell subsets often show different metabolic characteristics, various immune cell functions are closely related to fatty acids, including providing energy, providing synthetic materials and transmitting signals. In the face of the current situation of poor therapeutic effects of tumour immunotherapy, combined application of targeted immune cell fatty acid metabolism seems to have good therapeutic potential, which is blocked at immune checkpoints. Combined application of adoptive cell therapy and cancer vaccines is reflected. Therefore, it is of great interest to explore the role of fatty acid metabolism in immune cells to discover new strategies for tumour immunotherapy and improve anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s41420-024-01807-9
  11. Front Immunol. 2023 ;14 1327977
    Reduced mitochondrial respiration in peripheral T cells after paediatric heamatopoietic stem cell transplantation.
    Kasper Mølgaard, Katrine Kielsen, Marianne Ifversen, Özcan Met, Inge Marie Svane, Klaus Müller.
       Background: Recovery and functional differentiation of T-cell subsets are central for the development of immune function and complications after allogeneic hematopoietic stem cell transplantation (HSCT), but little is known about the cellular respiration and factors influencing T-cell metabolic fitness during immune maturation after HSCT.
    Method: We included 20 HSCT patients and analysed mitochondrial oxidative phosphorylation and mitochondrial fitness in peripheral blood mononuclear cell samples collected at days +90 and +180 after HSCT.
    Results: Phenotypic analysis revealed lower overall T-cell counts, lower CD4+/CD8+ ratio and a skewed distribution of early T-cell subsets at day +90, gradually recovering by day +180. Although ATP turnover in HSCT patients was similar to healthy controls, the spare respiratory capacity (SRC) of T cells, reflecting the available energy reserve, was significantly reduced at day +90 and +180 compared to healthy controls. This reduction in SRC was not correlated with the occurrence of acute graft-versus-host disease (aGVHD), the intensity of conditioning regimens and markers of T-cell exhaustion.
    Conclusion: We found significantly depressed SRC until six months post-HSCT, but we were not able to identify transplant-related risk factors or associations with the clinical outcome.
    Keywords:  T cells; acute graft-versus-host disease; hematopoietic stem cell transplantation; mitochondrial fitness; real-time metabolism; spare respiratory capacity
    DOI:  https://doi.org/10.3389/fimmu.2023.1327977
  12. Genes Immun. 2024 Jan 22.
    Take my breath away-mitochondrial dysfunction drives CD8+ T cell exhaustion.
    Felix Clemens Richter, Mariia Saliutina, Ahmed N Hegazy, Andreas Bergthaler.
      
    DOI:  https://doi.org/10.1038/s41435-023-00233-8
  13. Biomed Pharmacother. 2024 Jan 24. pii: S0753-3322(24)00053-2. [Epub ahead of print]171 116172
    Astragalus polysaccharide ameliorates CD8+ T cell dysfunction through STAT3/Gal-3/LAG3 pathway in inflammation-induced colorectal cancer.
    Qiuyi Li, Chonghao Zhang, Guichuan Xu, Xuekai Shang, Xinmei Nan, Yalan Li, Jiajing Liu, Yanfei Hong, Qing Wang, Guiying Peng.
      Chronic inflammation can promote cancer development as observed in inflammation-induced colorectal cancer (CRC). However, the poor treatment outcomes emphasize the need for effective treatment. Astragalus polysaccharide (APS), a vital component of the natural drug Astragalus, has anti-tumor effects by inhibiting cancer cell proliferation and enhancing immune function. In this study, we found that APS effectively suppressed CRC development through activating CD8+ T cells and reversing its inhibitory state in the tumor microenvironment (TME) of AOM/DSS inflammation-induced CRC mice. Network pharmacology and clinical databases suggested that the STAT3/ Galectin-3(Gal-3)/LAG3 pathway might be APS's potential target for treating CRC and associated with CD8+ T cell dysfunction. In vivo experiments showed that APS significantly reduced phosphorylated STAT3 and Gal-3 levels in tumor cells, as well as LAG3 in CD8+ T cells. Co-culture experiments with MC38 and CD8+ T cells demonstrated that APS decreased the expression of co-inhibitory receptor LAG3 in CD8+ T cells by targeting STAT3/Gal-3 in MC38 cells. Mechanism investigations revealed that APS specifically improved CD8+ T cell function through modulation of the STAT3/Gal-3/LAG3 pathway to inhibit CRC development, providing insights for future clinical development of natural anti-tumor drugs and immunotherapies as a novel strategy combined with immune checkpoint inhibitors (ICIs).
    Keywords:  Astragalus Polysaccharide; CD8(+) T cell dysfunction; Colorectal cancer; Galectin-3; LAG3; STAT3
    DOI:  https://doi.org/10.1016/j.biopha.2024.116172
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