bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–11–26
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.
  2. Clonally expanded memory CD8+ T cells accumulate in atherosclerotic plaques and are pro-atherogenic in aged mice.
  3. ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma.
  4. Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.
  5. Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function.
  6. Here be dragons: A universal profile of recent T-cell (hyper)activation?
  7. Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.
  8. FOXO1 is a master regulator of CAR T memory programming.
  9. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.
  1. Biochim Biophys Acta Rev Cancer. 2023 Nov 20. pii: S0304-419X(23)00171-3. [Epub ahead of print] 189022
    Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.
    Sirui Zhang, Xiaozhen Zhang, Hanshen Yang, Tingbo Liang, Xueli Bai.
      Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.
    Keywords:  Adoptive cell transfer therapy; Glucose metabolism; Immune checkpoint; Metabolic reprogramming; T cell; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189022
  2. Nat Aging. 2023 Nov 23.
    Clonally expanded memory CD8+ T cells accumulate in atherosclerotic plaques and are pro-atherogenic in aged mice.
    Daniel J Tyrrell, Kathleen M Wragg, Judy Chen, Hui Wang, Jianrui Song, Muriel G Blin, Chase Bolding, Donald Vardaman, Kara Giles, Harrison Tidwell, Md Akkas Ali, Abhinav Janappareddi, Sherri C Wood, Daniel R Goldstein.
      Aging is a strong risk factor for atherosclerosis and induces accumulation of memory CD8+ T cells in mice and humans. Biological changes that occur with aging lead to enhanced atherosclerosis, yet the role of aging on CD8+ T cells during atherogenesis is unclear. In this study, using femle mice, we found that depletion of CD8+ T cells attenuated atherogenesis in aged, but not young, animals. Furthermore, adoptive transfer of splenic CD8+ T cells from aged wild-type, but not young wild-type, donor mice significantly enhanced atherosclerosis in recipient mice lacking CD8+ T cells. We also characterized T cells in healthy and atherosclerotic young and aged mice by single-cell RNA sequencing. We found specific subsets of age-associated CD8+ T cells, including a Granzyme K+ effector memory subset, that accumulated and was clonally expanded within atherosclerotic plaques. These had transcriptomic signatures of T cell activation, migration, cytotoxicity and exhaustion. Overall, our study identified memory CD8+ T cells as therapeutic targets for atherosclerosis in aging.
    DOI:  https://doi.org/10.1038/s43587-023-00515-w
  3. Cancers (Basel). 2023 Nov 12. pii: 5377. [Epub ahead of print]15(22):
    ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma.
    Le Zhang, Yueyuan Zheng, Wenwen Chien, Benjamin Ziman, Sandrine Billet, H Phillip Koeffler, De-Chen Lin, Neil A Bhowmick.
      ARID1A, a member of the chromatin remodeling SWI/SNF complex, is frequently lost in many cancer types, including esophageal adenocarcinoma (EAC). Here, we study the impact of ARID1A deficiency on the anti-tumor immune response in EAC. We find that EAC tumors with ARID1A mutations are associated with enhanced tumor-infiltrating CD8+ T cell levels. ARID1A-deficient EAC cells exhibit heightened IFN response signaling and promote CD8+ T cell recruitment and cytolytic activity. Moreover, we demonstrate that ARID1A regulates fatty acid metabolism genes in EAC, showing that fatty acid metabolism could also regulate CD8+ T cell recruitment and CD8+ T cell cytolytic activity in EAC cells. These results suggest that ARID1A deficiency shapes both tumor immunity and lipid metabolism in EAC, with significant implications for immune checkpoint blockade therapy in EAC.
    Keywords:  ARID1A; CD8+ T cells; IFN response; esophageal adenocarcinoma; lipid metabolism; tumor immunity
    DOI:  https://doi.org/10.3390/cancers15225377
  4. Adv Sci (Weinh). 2023 Nov 21. e2303664
    Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.
    Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Anwari Akhter, Alyssa Schami, Kevin Chiem, Russell Ault, Hao Zhang, Hong Cai, Alison Whigham, Jennifer Delgado, Amberlee Hicks, Philip S Tsao, Jonathan Gelfond, Luis Martinez-Sobrido, Yufeng Wang, Jordi B Torrelles, Joanne Turner.
      Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non-activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito-transferred aged CD4+ T cells showed improvements in activation-induced TCR-signaling kinetics displaying markers of activation (CD25), increased IL-2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG-KO) showed that adoptive transfer of mito-transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.
    Keywords:  CD4+ T cells; adaptive immunity; aging immunology; immunometabolism; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/advs.202303664
  5. J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02516-4. [Epub ahead of print] 105488
    Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function.
    Erica L Braverman, Margaret A McQuaid, Herbert Schuler, Mengtao Qin, Sophia Hani, Keli Hippen, Darlene A Monlish, Andrea K Dobbs, Manda J Ramsey, Felicia Kemp, Christopher Wittmann, Archana Ramgopal, Harrison Brown, Bruce Blazar, Craig A Byersdorfer.
      Cellular therapies are currently employed to treat a variety of disease processes. For T cell-based therapies, success often relies on the metabolic fitness of the T cell product, where cells with enhanced metabolic capacity demonstrate improved in vivo efficacy. AMP-activated protein kinase (AMPK) is a cellular energy sensor which combines environmental signals with cellular energy status to enforce efficient and flexible metabolic programming. We hypothesized that increasing AMPK activity in human T cells would augment their oxidative capacity, creating an ideal product for adoptive cellular therapies. Lentiviral transduction of the regulatory AMPKγ2 subunit stably enhanced intrinsic AMPK signaling and promoted mitochondrial respiration with increased basal oxygen consumption rates (OCR), higher maximal OCR, and augmented spare respiratory capacity. These changes were accompanied by increased proliferation and inflammatory cytokine production, particularly within restricted glucose environments. Introduction of AMPKγ2 into bulk CD4 T cells decreased RNA expression of canonical Th2 genes, including the cytokines IL-4 and IL-5, while introduction of AMPKγ2 into individual Th subsets universally favored pro-inflammatory cytokine production and a down-regulation of IL-4 production in Th2 cells. When AMPKγ2 was overexpressed in regulatory T cells (Treg), both in vitro proliferation and suppressive capacity increased. Together, these data suggest that augmenting intrinsic AMPK signaling via overexpression of AMPKγ2 can improve the expansion and functional potential of human T cells for use in a variety of adoptive cellular therapies.
    DOI:  https://doi.org/10.1016/j.jbc.2023.105488
  6. J Allergy Clin Immunol. 2023 Nov 20. pii: S0091-6749(23)01468-9. [Epub ahead of print]
    Here be dragons: A universal profile of recent T-cell (hyper)activation?
    Michael B Jordan.
      
    Keywords:  CD38; T-cell immune regulation
    DOI:  https://doi.org/10.1016/j.jaci.2023.11.010
  7. Antioxidants (Basel). 2023 Nov 02. pii: 1956. [Epub ahead of print]12(11):
    Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.
    Angelica Giuliani, Anna Maria Giudetti, Daniele Vergara, Laura Del Coco, Deborah Ramini, Sara Caccese, Matilde Sbriscia, Laura Graciotti, Gianluca Fulgenzi, Luca Tiano, Francesco Paolo Fanizzi, Fabiola Olivieri, Maria Rita Rippo, Jacopo Sabbatinelli.
      Cellular senescence is closely linked to endothelial dysfunction, a key factor in age-related vascular diseases. Senescent endothelial cells exhibit a proinflammatory phenotype known as SASP, leading to chronic inflammation (inflammaging) and vascular impairments. Albeit in a state of permanent growth arrest, senescent cells paradoxically display a high metabolic activity. The relationship between metabolism and inflammation is complex and varies across cell types and senescence inductions. While some cell types shift towards glycolysis during senescence, others favor oxidative phosphorylation (OXPHOS). Despite the high availability of oxygen, quiescent endothelial cells (ECs) tend to rely on glycolysis for their bioenergetic needs. However, there are limited data on the metabolic behavior of senescent ECs. Here, we characterized the metabolic profiles of young and senescent human umbilical vein endothelial cells (HUVECs) to establish a possible link between the metabolic status and the proinflammatory phenotype of senescent ECs. Senescent ECs internalize a smaller amount of glucose, have a lower glycolytic rate, and produce/release less lactate than younger cells. On the other hand, an increased fatty acid oxidation activity was observed in senescent HUVECs, together with a greater intracellular content of ATP. Interestingly, blockade of glycolysis with 2-deoxy-D-glucose in young cells resulted in enhanced production of proinflammatory cytokines, while the inhibition of carnitine palmitoyltransferase 1 (CPT1), a key rate-limiting enzyme of fatty acid oxidation, ameliorated the SASP in senescent ECs. In summary, metabolic changes in senescent ECs are complex, and this research seeks to uncover potential strategies for modulating these metabolic pathways to influence the SASP.
    Keywords:  endothelial cells; fatty acid oxidation; glycolysis; senescence; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.3390/antiox12111956
  8. Res Sq. 2023 Nov 07. pii: rs.3.rs-2802998. [Epub ahead of print]
    FOXO1 is a master regulator of CAR T memory programming.
    Crystal Mackall, Alexander Doan, Katherine Mueller, Andy Chen, Geoffrey Rouin, Bence Daniel, John Lattin, Yingshi Chen, Brett Mozarsky, Martina Markovska, Jose Arias-Umana, Robert Robert Hapke, Inyoung Jung, Peng Xu, Dorota Klysz, Malek Bashti, Patrick Quinn, Katalin Sandor, Wenxi Zhang, Junior Hall, Caleb Lareau, Stephan Grupp, Joseph Fraietta, Elena Sotillo, Ansuman Satpathy, Evan Weber.
      Poor CAR T persistence limits CAR T cell therapies for B cell malignancies and solid tumors 1,2 . The expression of memory-associated genes such as TCF7 (protein name TCF1) is linked to response and long-term persistence in patients 3-7 , thereby implicating memory programs in therapeutic efficacy. Here, we demonstrate that the pioneer transcription factor, FOXO1, is responsible for promoting memory programs and restraining exhaustion in human CAR T cells. Pharmacologic inhibition or gene editing of endogenous FOXO1 in human CAR T cells diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype, and impaired antitumor activity in vitro and in vivo . FOXO1 overexpression induced a gene expression program consistent with T cell memory and increased chromatin accessibility at FOXO1 binding motifs. FOXO1-overexpressing cells retained function, memory potential, and metabolic fitness during settings of chronic stimulation and exhibited enhanced persistence and antitumor activity in vivo. Paradoxically, TCF1 overexpression failed to enforce canonical memory programs or enhance CAR T cell potency. Importantly, endogenous FOXO1 activity correlated with CAR T and TIL responses in patients, underscoring its clinical relevance in cancer immunotherapy. Our results demonstrate that memory reprogramming through FOXO1 can enhance the persistence and potency of human CAR T cells and highlights the utility of pioneer factors, which bind condensed chromatin and induce local epigenetic remodeling, for optimizing therapeutic T cell states.
    DOI:  https://doi.org/10.21203/rs.3.rs-2802998/v1
  9. Nature. 2023 Nov 22.
    Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.
    Hao Fan, Siyuan Xia, Junhong Xiang, Yuancheng Li, Matthew O Ross, Seon Ah Lim, Fan Yang, Jiayi Tu, Lishi Xie, Urszula Dougherty, Freya Q Zhang, Zhong Zheng, Rukang Zhang, Rong Wu, Lei Dong, Rui Su, Xiufen Chen, Thomas Althaus, Peter A Riedell, Patrick B Jonker, Alexander Muir, Gregory B Lesinski, Sarwish Rafiq, Madhav V Dhodapkar, Wendy Stock, Olatoyosi Odenike, Anand A Patel, Joseph Opferman, Takemasa Tsuji, Junko Matsuzaki, Hardik Shah, Brandon Faubert, Shannon E Elf, Brian Layden, B Marc Bissonnette, Yu-Ying He, Justin Kline, Hui Mao, Kunle Odunsi, Xue Gao, Hongbo Chi, Chuan He, Jing Chen.
      Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.
    DOI:  https://doi.org/10.1038/s41586-023-06749-3
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