bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–10–09
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.
  2. Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage.
  3. GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.
  4. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy.
  5. Lipid metabolic features of T cells in the Tumor Microenvironment.
  6. Autophagic flux restoration of senescent T cells improves antitumor activity of TCR-engineered T cells.
  7. A single administration of hIL-7-hyFc induces long-lasting T-cell expansion with maintained functions and TCR diversity.
  8. SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.
  9. The how and when of metabolic health.
  10. Technology meets TILs: Deciphering T cell function in the -omics era.
  11. Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.
  12. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
  13. Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma.
  1. EMBO Rep. 2022 Oct 04. e55399
    Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.
    Pedro M O Ventura, Milica Gakovic, Berenice A Fischer, Laura Spinelli, Giorgia Rota, Shalini Pathak, Hanif J Khameneh, Alessandro Zenobi, Sarah Thomson, Walter Birchmeier, Doreen A Cantrell, Greta Guarda.
      Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.
    Keywords:  PD-1 checkpoint blockade; Ptpn11; Ptpn6; T cell exhaustion
    DOI:  https://doi.org/10.15252/embr.202255399
  2. Front Immunol. 2022 ;13 976628
    Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage.
    Elisabetta Cribioli, Greta Maria Paola Giordano Attianese, Pierpaolo Ginefra, Amandine Signorino-Gelo, Romain Vuillefroy de Silly, Nicola Vannini, Christoph Hess, Melita Irving, George Coukos.
      Despite the tremendous success of adoptive T-cell therapies (ACT) in fighting certain hematologic malignancies, not all patients respond, a proportion experience relapse, and effective ACT of most solid tumors remains elusive. In order to improve responses to ACT suppressive barriers in the solid tumor microenvironment (TME) including insufficient nutrient availability must be overcome. Here we explored how enforced expression of the high-affinity glucose transporter GLUT3 impacted tumor-directed T cells. Overexpression of GLUT3 in primary murine CD8+ T cells enhanced glucose uptake and increased glycogen and fatty acid storage, and was associated with increased mitochondrial fitness, reduced ROS levels, higher abundance of the anti-apoptotic protein Mcl-1, and better resistance to stress. Importantly, GLUT3-OT1 T cells conferred superior control of B16-OVA melanoma tumors and, in this same model, significantly improved survival. Moreover, a proportion of treated mice were cured and protected from re-challenge, indicative of long-term T cell persistence and memory formation. Enforcing expression of GLUT3 is thus a promising strategy to improve metabolic fitness and sustaining CD8+ T cell effector function in the context of ACT.
    Keywords:  T cell engineering; adoptive cell therapy; glucose; immunotherapy; metabolism; tumor
    DOI:  https://doi.org/10.3389/fimmu.2022.976628
  3. Nat Metab. 2022 Oct 03.
    GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.
    Siwen Kang, Lingling Liu, Tingting Wang, Matthew Cannon, Penghui Lin, Teresa W-M Fan, David A Scott, Hsin-Jung Joyce Wu, Andrew N Lane, Ruoning Wang.
      γ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB metabolism is controlled to mediate such functions remains elusive. Here we show that GAB is one of the most abundant metabolites in CD4+ T helper 17 (TH17) and induced T regulatory (iTreg) cells. GAB functions as a bioenergetic and signalling gatekeeper by reciprocally controlling pro-inflammatory TH17 cell and anti-inflammatory iTreg cell differentiation through distinct mechanisms. 4-Aminobutyrate aminotransferase (ABAT) funnels GAB into the tricarboxylic acid (TCA) cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activity in iTreg cells enables GAB to be exported to the extracellular environment where it acts as an autocrine signalling metabolite that promotes iTreg cell differentiation. Accordingly, ablation of ABAT activity in T cells protects against experimental autoimmune encephalomyelitis (EAE) progression. Conversely, ablation of GABAA receptor in T cells worsens EAE. Our results suggest that the cell-autonomous control of GAB on CD4+ T cells is bimodal and consists of the sequential action of two processes, ABAT-dependent mitochondrial anaplerosis and the receptor-dependent signalling response, both of which are required for T cell-mediated inflammation.
    DOI:  https://doi.org/10.1038/s42255-022-00638-1
  4. J Immunother Cancer. 2022 Oct;pii: e005020. [Epub ahead of print]10(10):
    Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy.
    Xia Liu, Fusheng Si, David Bagley, Feiya Ma, Yuanqin Zhang, Yan Tao, Emily Shaw, Guangyong Peng.
       BACKGROUND: Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.
    METHODS: Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy.
    RESULTS: We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.
    CONCLUSIONS: These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.
    Keywords:  Immunotherapy; Melanoma; T-Lymphocytes; Tumor Escape; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2022-005020
  5. Lipids Health Dis. 2022 Oct 06. 21(1): 94
    Lipid metabolic features of T cells in the Tumor Microenvironment.
    Wanshuang Lou, Chaoju Gong, Zhuoni Ye, Ynayan Hu, Minjing Zhu, Zejun Fang, Huihui Xu.
      The tumor microenvironment (TME) is characterized by discrete changes in metabolic features of cancer and immune cells, with various implications. Cancer cells take up most of the available glucose to support their growth, thereby leaving immune cells with insufficient nutrients to expand. In the relative absence of glucose, T cells switch the metabolic program to lipid-based sources, which is pivotal to T-cell differentiation and activation in nutrient-stressed TME. Although consumption of lipids should provide an alternative energy source to starving T cells, a literature survey has revealed that it may not necessarily lead to antitumor responses. Different subtypes of T cells behave differently in various lipid overload states, which widely depends upon the kind of free fatty acids (FFA) engulfed. Key lipid metabolic genes provide cytotoxic T cells with necessary nutrients for proliferation in the absence of glucose, thereby favoring antitumor immunity, but the same genes cause immune evasion in Tmem and Treg. This review aims to detail the complexity of differential lipid metabolism in distinct subtypes of T cells that drive the antitumor or pro-tumor immunity in specific TME states. We have identified key drug targets related to lipid metabolic rewiring in TME.
    Keywords:  CD36; Lipid; PD-L1/2; T-cells; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1186/s12944-022-01705-y
  6. Clin Transl Immunology. 2022 ;11(9): e1419
    Autophagic flux restoration of senescent T cells improves antitumor activity of TCR-engineered T cells.
    Chaoting Zhang, Yizhe Sun, Shance Li, Luyan Shen, Xia Teng, Yefei Xiao, Ping Zhou, Zheming Lu.
       Objectives: Although adoptive cell therapy with T-cell receptor-engineered T cells (TCR-Ts) has mediated effective antitumor responses in several cancers, senescence of T cells could impair the therapeutic effect of TCR-Ts. Thus, it is essential to elucidate the characteristics of senescent TCR-Ts and how to subsequently improve their antitumor effect. Here, we focused on the influence of autophagy on TCR-Ts, since autophagy is tightly associated with the regulation of T-cell activation, proliferation and differentiation.
    Methods: We first evaluated autophagy level of senescent TCR-Ts, and then the senescent TCR-Ts were expanded in vitro for 7 days with and without spermidine treatment, respectively. Furthermore, the proliferative potential, phenotypical characteristics and functionality of the propagated senescent TCR-Ts were analysed in vitro and in vivo after 7-day ex vivo expansion.
    Results: We found that autophagic flux of senescent TCR-T cells was significantly impaired. The restoration of autophagic flux via spermidine treatment reduced the expression of inhibitory immunoreceptors (PD-1, TIM-3 or LAG-3), enhanced proliferation and effector functions and subsequently demonstrated the superior in vitro and in vivo antitumor activity of TCR-Ts.
    Conclusion: These data suggest that spermidine treatment presents an opportunity to improve the antitumor effect of TCR-Ts for the treatment of solid tumors.
    Keywords:  TCR‐T; T‐cell receptor; autophagy; senescence; spermidine
    DOI:  https://doi.org/10.1002/cti2.1419
  7. Blood Adv. 2022 Oct 07. pii: bloodadvances.2021006591. [Epub ahead of print]
    A single administration of hIL-7-hyFc induces long-lasting T-cell expansion with maintained functions and TCR diversity.
    Sojeong Kim, Sang Won Lee, June-Young Koh, Donghoon Choi, Minkyu Heo, Jae-Yong Chung, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Howard Lee, Eui-Cheol Shin, Su-Hyung Park.
      Interleukin-7 (IL-7) is an essential cytokine for T-cell homeostatic proliferation and maintenance. Clinical studies have shown the potential benefits of IL-7 therapy in various diseases associated with lymphopenia. However, the kinetics of the T-cell response to a single administration of IL-7 in humans have not been fully elucidated. Here, we investigated the effects of Fc-fused long-acting recombinant human IL-7 (hIL-7-hyFc, efineptakin alfa) on lymphocytes in healthy adults after a single subcutaneous or intramuscular administration. Administration of hIL-7-hyFc increased the CD8+ and CD4+ T-cell numbers up to 2.5-fold, with corresponding upregulation of Ki-67 and Bcl-2 expression, peaking at day 3 or 7. Regulatory T cells did not expand. Among CD8+ and CD4+ T cells, all T-cell subsets (TN, TEM, TCM, TEMRA, and TSCM) increased for 56 days. The TCR repertoire diversity of naïve CD8+ and CD4+ T cells was increased by hIL-7-hyFc, while the memory T-cell subsets did not differ between D56 and D0. Transcriptomic analysis revealed that hIL-7-hyFc induced robust T-cell expansion without changes in gene expression profiles associated with T-cell functions or genes related to T-cell exhaustion, senescence, and anergy. The effector functions of antigen-specific CD8+ T cells were preserved after hIL-7-hyFc administration. Our results suggest that hIL-7-hyFc administration induced a sustained increase in the numbers of CD8+ and CD4+ T cells, but not regulatory T cells, without qualitative changes. These results support the potential of hIL-7-hyFc as a treatment for patients with compromised T-cell immunity or as a vaccine adjuvant.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006591
  8. Aging Cell. 2022 Oct 05. e13721
    SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.
    Rashpal S Dhillon, Yiming Amy Qin, Paul R van Ginkel, Vivian X Fu, James M Vann, Alexis J Lawton, Cara L Green, Fúlvia B Manchado-Gobatto, Claudio A Gobatto, Dudley W Lamming, Tomas A Prolla, John M Denu.
      Mitochondrial NAD+ -dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/- ) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.
    Keywords:  aerobic fitness; calorie restriction; fatty acid oxidation; fuel switching; lifespan; mitochondrial acetylation; mitochondrial respiration; sirtuins
    DOI:  https://doi.org/10.1111/acel.13721
  9. Cell Metab. 2022 Oct 04. pii: S1550-4131(22)00406-5. [Epub ahead of print]34(10): 1411-1412
    The how and when of metabolic health.
    Rosalind Mott, Allyson Evans, Mari-Carmen Fernandez-Aguera, Amber Mueller.
      
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.016
  10. Cancer Cell. 2022 Oct 05. pii: S1535-6108(22)00440-8. [Epub ahead of print]
    Technology meets TILs: Deciphering T cell function in the -omics era.
    William H Hudson, Andreas Wieland.
      T cells are at the center of cancer immunology because of their ability to recognize mutations in tumor cells and directly mediate cancer cell killing. Immunotherapies to rejuvenate exhausted T cell responses have transformed the clinical management of several malignancies. In parallel, the development of novel multidimensional analysis platforms, such as single-cell RNA sequencing and high-dimensional flow cytometry, has yielded unprecedented insights into immune cell biology. This convergence has revealed substantial heterogeneity of tumor-infiltrating immune cells in single tumors, across tumor types, and among individuals with cancer. Here we discuss the opportunities and challenges of studying the complex tumor microenvironment with -omics technologies that generate vast amounts of data, highlighting the opportunities and limitations of these technologies with a particular focus on interpreting high-dimensional studies of CD8+ T cells in the tumor microenvironment.
    Keywords:  CD4; CD8; PD-1; T cell; bystander; cancer immunology; flow cytometry; immunotherapy; scRNA-seq; techniques; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.ccell.2022.09.011
  11. Front Pharmacol. 2022 ;13 972397
    Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.
    Chao Jin, Bei-Bei Gao, Wen-Jing Zhou, Bao-Jing Zhao, Xing Fang, Chun-Lan Yang, Xiao-Hua Wang, Quan Xia, Ting-Ting Liu.
      Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.
    Keywords:  G protein-coupled receptor kinase 2; PI3K-AKT axis; autoimmune hepatitis; glycolipid metabolism; hydroxychloroquine; regulatory T cells
    DOI:  https://doi.org/10.3389/fphar.2022.972397
  12. Cell Metab. 2022 Sep 28. pii: S1550-4131(22)00395-3. [Epub ahead of print]
    Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
    Erika Fernández-Vizarra, Sandra López-Calcerrada, Ana Sierra-Magro, Rafael Pérez-Pérez, Luke E Formosa, Daniella H Hock, María Illescas, Ana Peñas, Michele Brischigliaro, Shujing Ding, Ian M Fearnley, Charalampos Tzoulis, Robert D S Pitceathly, Joaquín Arenas, Miguel A Martín, David A Stroud, Massimo Zeviani, Michael T Ryan, Cristina Ugalde.
      The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.
    Keywords:  COX7A1–2; SCAFI/COX7RP/COX7A2L; bioenergetics; glycolysis; metabolic switch; mitochondria; oxidative metabolism; pyruvate dehydrogenase; respiratory chain organizations; respiratory supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.005
  13. World J Gastrointest Oncol. 2022 Sep 15. 14(9): 1887-1891
    Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma.
    Chun-Ye Zhang, Shuai Liu, Ming Yang.
      Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Factors including carcinogens, infection of hepatitis viruses, alcohol abuse, and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression. Immunotherapy is one of the most powerful tools for unresectable HCC treatment in patients. CD8+ T cells are a major immune component in the tumor microenvironment with cytotoxic effects against cancer cells. However, these CD8+ T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing-3, and/or lymphocyte-activation gene 3, producing low levels of perforin (PRF1) and granzyme B (GZMB), as well as anti-tumor cytokines, such as interferon gamma and tumor necrosis factor alpha. In the referenced study, the authors also showed that deprivation of glutamine decreased the antitumor function of CD8+ T cells, as well as the production of PRF1 and GZMB. However, the role of each amino acid in T cell function and exhaustion may depend on tumor type and tumor microenvironment, including the source of other nutrients. Overall, amino acids or other nutrient metabolites in the tumor microenvironment play a pivotal role in both tumor growth and immune response.
    Keywords:  Amino acids; Hepatocellular carcinoma; Metabolism; T cell function; Tumor microenvironment
    DOI:  https://doi.org/10.4251/wjgo.v14.i9.1887
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