bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–02–05
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
  2. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.
  3. Metabolic function of autophagy is essential for cell survival.
  4. Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.
  5. High glucose promotes regulatory T cell differentiation.
  6. Interleukin-2 and PD-1 synergistically modify T cell exhaustion programs.
  7. G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma.
  8. CD8 T cells are forever.
  9. T cells feed into cancer immune escape.
  10. CD8+ T cells pass the acid test.
  11. FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans.
  12. Age-Related Changes in Female Murine Reproductive Mucosa with respect to γδ T Cell Presence.
  13. Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.
  14. BRCA1 deficiency in mature CD8+ T lymphocytes impairs antitumor immunity.
  1. Nat Metab. 2023 Jan 30.
    Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
    Hongcheng Cheng, Yajing Qiu, Yue Xu, Li Chen, Kaili Ma, Mengyuan Tao, Luke Frankiw, Hongli Yin, Ermei Xie, Xiaoli Pan, Jing Du, Zhe Wang, Wenjie Zhu, Lu Chen, Lianjun Zhang, Guideng Li.
      The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.
    DOI:  https://doi.org/10.1038/s42255-022-00730-6
  2. Nat Commun. 2023 Feb 02. 14(1): 86
    Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.
    Marcel P Trefny, Nicole Kirchhammer, Priska Auf der Maur, Marina Natoli, Dominic Schmid, Markus Germann, Laura Fernandez Rodriguez, Petra Herzig, Jonas Lötscher, Maryam Akrami, Jane C Stinchcombe, Michal A Stanczak, Andreas Zingg, Melanie Buchi, Julien Roux, Romina Marone, Leyla Don, Didier Lardinois, Mark Wiese, Lukas T Jeker, Mohamed Bentires-Alj, Jérémie Rossy, Daniela S Thommen, Gillian M Griffiths, Heinz Läubli, Christoph Hess, Alfred Zippelius.
      Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-022-35583-w
  3. Autophagy. 2023 Feb 01. 1-3
    Metabolic function of autophagy is essential for cell survival.
    Lucia Sedlackova, Tetsushi Kataura, Sovan Sarkar, Viktor I Korolchuk.
      Age-related human pathologies present with a multitude of molecular and metabolic phenotypes, which individually or synergistically contribute to tissue degeneration. However, current lack of understanding of the interdependence of these molecular pathologies limits the potential range of existing therapeutic intervention strategies. In our study, we set out to understand the chain of molecular events, which underlie the loss of cellular viability in macroautophagy/autophagy deficiency associated with aging and age-related disease. We discover a novel axis linking autophagy, a cellular waste disposal pathway, and a metabolite, nicotinamide adenine dinucleotide (NAD). The axis connects multiple organelles, molecules and stress response pathways mediating cellular demise when autophagy becomes dysfunctional. By elucidating the steps on the path from efficient mitochondrial recycling to NAD maintenance and ultimately cell viability, we highlight targets potentially receptive to therapeutic interventions in a range of genetic and age-related diseases associated with autophagy dysfunction.Abbreviations: IMM: inner mitochondrial membrane; NAD: nicotinamide dinucleotide; OXPHOS: oxidative phosphorylation; PARP: poly(ADP-ribose) polymerase; ROS: reactive oxygen species.
    Keywords:  Aging; DNA damage; NAD; PARP; ROS; autophagy; mitochondria; mitophagy; sirtuins
    DOI:  https://doi.org/10.1080/15548627.2023.2165753
  4. Nat Immunol. 2023 Feb 02.
    Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.
    Joy Edwards-Hicks, Petya Apostolova, Joerg M Buescher, Hannes Maib, Michal A Stanczak, Mauro Corrado, Ramon I Klein Geltink, Maria Elena Maccari, Matteo Villa, Gustavo E Carrizo, David E Sanin, Francesc Baixauli, Beth Kelly, Jonathan D Curtis, Fabian Haessler, Annette Patterson, Cameron S Field, George Caputa, Ryan L Kyle, Melanie Soballa, Minsun Cha, Harry Paul, Jacob Martin, Katarzyna M Grzes, Lea Flachsmann, Michael Mitterer, Liang Zhao, Frances Winkler, David Ali Rafei-Shamsabadi, Frank Meiss, Bertram Bengsch, Robert Zeiser, Daniel J Puleston, David O'Sullivan, Edward J Pearce, Erika L Pearce.
      How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIPn with 3-4 double bonds), Teff cells have unique PIPn marked by saturated fatty acyl chains (0-2 double bonds). PIPn are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP2) exclusively supported signaling immediately upon T cell antigen receptor activation. In late Teff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP2 into downstream mediators, waned, and saturated PIPn became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP2 with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIPn impaired Teff cell fitness and function, even in cells with abundant polyunsaturated PIPn. Glucose was the substrate for de novo PIPn synthesis, and was rapidly utilized for saturated PIP2 generation. Thus, separate PIPn pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-023-01419-y
  5. PLoS One. 2023 ;18(2): e0280916
    High glucose promotes regulatory T cell differentiation.
    Elise Pitmon, Eileen Victoria Meehan, Elham Ahmadi, Adam J Adler, Kepeng Wang.
      The consumption of processed foods and sugary sodas in Western diets correlates with an increased incidence of obesity, metabolic syndromes such as type 2 diabetes, cardiovascular diseases, and autoimmune diseases including inflammatory bowel disease and rheumatoid arthritis. All these diseases have an inflammatory component, of which T lymphocytes can play a critical role in driving. Much has been learned regarding the importance of sugar, particularly glucose, in fueling effector versus regulatory T cells that can promote or dampen inflammation, respectively. In particular, glucose and its metabolic breakdown products via glycolysis are essential for effector T cell differentiation and function, while fatty acid-fueled oxidative phosphorylation supports homeostasis and function of regulatory T cells. Nevertheless, a critical knowledge gap, given the prevalence of diabetes in Western societies, is the impact of elevated glucose concentrations on the balance between effector versus regulatory T cells. To begin addressing this, we cultured naïve CD4+ T cells with different concentrations of glucose, and examined their differentiation into effector versus regulatory lineages. Surprisingly, high glucose promoted regulatory T cell differentiation and inhibited Th1 effector differentiation. This skewing towards the regulatory lineage occurred via an indirect mechanism that depends on lactate produced by activated glycolytic T cells. Addition of lactate to the T cell differentiation process promotes the differentiation of Treg cells, and activates Akt/mTOR signaling cascade. Hence, our findings suggest the existence of a novel feedback mechanism in which lactate produced by activated, differentiating T cells skews their lineage commitment towards the regulatory fate.
    DOI:  https://doi.org/10.1371/journal.pone.0280916
  6. Am J Transplant. 2023 Jan 14. pii: S1600-6135(23)00011-4. [Epub ahead of print]
    Interleukin-2 and PD-1 synergistically modify T cell exhaustion programs.
    Paolo Cravedi, Xian C Li.
      
    DOI:  https://doi.org/10.1016/j.ajt.2023.01.002
  7. Nat Commun. 2023 Feb 02. 14(1): 563
    G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma.
    Maxine S Y Lam, Jose Antonio Reales-Calderon, Jin Rong Ow, Joey J Y Aw, Damien Tan, Ragavi Vijayakumar, Erica Ceccarello, Tommaso Tabaglio, Yan Ting Lim, Wang Loo Chien, Fritz Lai, Anthony Tan Tanoto, Qingfeng Chen, Radoslaw M Sobota, Giulia Adriani, Antonio Bertoletti, Ernesto Guccione, Andrea Pavesi.
      Engineered T cells transiently expressing tumor-targeting receptors are an attractive form of engineered T cell therapy as they carry no risk of insertional mutagenesis or long-term adverse side-effects. However, multiple rounds of treatment are often required, increasing patient discomfort and cost. To mitigate this, we sought to improve the antitumor activity of transient engineered T cells by screening a panel of small molecules targeting epigenetic regulators for their effect on T cell cytotoxicity. Using a model for engineered T cells targetting hepatocellular carcinoma, we find that short-term inhibition of G9a/GLP increases T cell antitumor activity in in vitro models and an orthotopic mouse model. G9a/GLP inhibition increases granzyme expression without terminal T cell differentiation or exhaustion and results in specific changes in expression of genes and proteins involved in pro-inflammatory pathways, T cell activation and cytotoxicity.
    DOI:  https://doi.org/10.1038/s41467-023-36160-5
  8. Sci Immunol. 2023 Feb 03. 8(80): eadg8279
    CD8 T cells are forever.
    Jonathan S Maltzman.
      Iterative acute stimulations can maintain CD8 T cells for longer than their organismal lifespan.
    DOI:  https://doi.org/10.1126/sciimmunol.adg8279
  9. Nat Rev Cancer. 2023 Feb 02.
    T cells feed into cancer immune escape.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-023-00550-0
  10. Nat Metab. 2023 Jan 30.
    CD8+ T cells pass the acid test.
    Ju Hee Oh, Anne-Sophie Archambault, Ramon I Klein Geltink.
      
    DOI:  https://doi.org/10.1038/s42255-023-00738-6
  11. Nat Commun. 2023 Feb 02. 14(1): 562
    FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans.
    Hyo Sub Choi, Ajay Bhat, Marshall B Howington, Megan L Schaller, Rebecca L Cox, Shijiao Huang, Safa Beydoun, Hillary A Miller, Angela M Tuckowski, Joy Mecano, Elizabeth S Dean, Lindy Jensen, Daniel A Beard, Charles R Evans, Scott F Leiser.
      Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling.
    DOI:  https://doi.org/10.1038/s41467-023-36181-0
  12. J Immunol Res. 2023 ;2023 3072573
    Age-Related Changes in Female Murine Reproductive Mucosa with respect to γδ T Cell Presence.
    Katarzyna Skulska, Anna Ewa Kędzierska, Małgorzata Krzyżowska, Grzegorz Chodaczek.
      Many studies have demonstrated a general decline and dysregulation in immune functions with age. It is not clear, however, how the aging affects the immune surveillance of the female reproductive tract (FRT) by γδ T cells, a unique population of T lymphocytes that was shown to regulate homeostasis of epithelial barriers. First, we analyzed γδ T cell presence in FRT in young (2 months) and old (18 months) wild-type (WT) C57BL/6 mice. We did not detect any changes in γδ T cell number nor distribution in the vaginas between the age groups, while in uteri, there was a twofold increase in γδ T cell number in aged mice. To check if γδ T lymphocytes regulate a metabolic and immune status of aging vaginal tissue, we compared the expression of 84 aging-associated genes in young and old WT and γδ T-cell-deficient (Tcrd -/-) mice. We discovered that only the Ltf (lactotransferrin) gene was downregulated in old Tcrd -/- mice. In both mouse strains, we found similar age-dependent changes in cytokine production upon vaginal inflammation due to Toll-like receptor 9 (TLR9) stimulation with CpG. With age in the vaginas, IL-1α and IL-17A levels increased while IL-6, IL-10, MCP-1, and IFNγ levels were diminished in response to CpG. Similar trends were observed in uteri. Interestingly, under the inflammatory state, the lack of γδ T cells in young individuals enhanced MCP-1 production in the vagina and decreased MCP-1 level in the uterus in old females. Our gene expression data point to an antimicrobial role of γδ T lymphocytes. The profile of secreted inflammatory cytokines shifted during aging toward the proinflammatory type, and γδ T cells played a modest fine-tuning role in immunoregulation in aged FRT. We believe this work expands our understanding of γδ T cell functions and the inflammaging in the murine reproductive epithelia.
    DOI:  https://doi.org/10.1155/2023/3072573
  13. bioRxiv. 2023 Jan 07. pii: 2023.01.06.522784. [Epub ahead of print]
    Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.
    Eric Hee Jun Lee, Cody Cullen, John P Murad, Diana Gumber, Anthony K Park, Jason Yang, Lawrence A Stern, Lauren N Adkins, Gaurav Dhapola, Brenna Gittins, Wen Chung-Chang, Catalina Martinez, Yanghee Woo, Mihaela Cristea, Lorna Rodriguez-Rodriguez, Jun Ishihara, John K Lee, Stephen J Forman, Leo D Wang, Saul J Priceman.
      Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumor microenvironments. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies, which are being harnessed to improve solid tumor CAR T cell therapies. Here, we describe fully optimized CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) for the treatment of solid tumors, identifying the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. These findings have culminated into a phase 1 trial evaluating safety, feasibility, and bioactivity of TAG72-CAR T cells for the treatment of patients with advanced ovarian cancer ( NCT05225363 ). Preclinically, we found that CAR T cell-mediated IFNγ production facilitated by IL-12 signaling was required for tumor cell killing, which was recapitulated by expressing an optimized membrane-bound IL-12 (mbIL12) molecule on CAR T cells. Critically, mbIL12 cell surface expression and downstream signaling was induced and sustained only following CAR T cell activation. CAR T cells with mbIL12 demonstrated improved antigen-dependent T cell proliferation and potent cytotoxicity in recursive tumor cell killing assays in vitro and showed robust in vivo anti-tumor efficacy in human xenograft models of ovarian cancer peritoneal metastasis. Further, locoregional administration of TAG72-CAR T cells with antigen-dependent IL-12 signaling promoted durable anti-tumor responses against both regional and systemic disease in mice and was associated with improved systemic T cell persistence. Our study features a clinically-applicable strategy to improve the overall efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting both regional and systemic disease.
    DOI:  https://doi.org/10.1101/2023.01.06.522784
  14. J Immunother Cancer. 2023 Feb;pii: e005852. [Epub ahead of print]11(2):
    BRCA1 deficiency in mature CD8+ T lymphocytes impairs antitumor immunity.
    Bogang Wu, Leilei Qi, Huai-Chin Chiang, Haihui Pan, Xiaowen Zhang, Alexandra Greenbaum, Elizabeth Stark, Li-Ju Wang, Yidong Chen, Bassem R Haddad, Dionyssia Clagett, Claudine Isaacs, Richard Elledge, Anelia Horvath, Yanfen Hu, Rong Li.
      Women with BRCA1 germline mutations have approximately an 80% lifetime chance of developing breast cancer. While the tumor suppressor function of BRCA1 in breast epithelium has been studied extensively, it is not clear whether BRCA1 deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse Brca1 knockout (KO) in mature T lymphocytes compromises host antitumor immune response to transplanted syngeneic mouse mammary tumors. T cell adoptive transfer further corroborates CD8+ T cell-intrinsic impact of Brca1 KO on antitumor adaptive immunity. T cell-specific Brca1 KO mice exhibit fewer total CD8+, more exhausted, reduced cytotoxic, and reduced memory tumor-infiltrating T cell populations. Consistent with the preclinical data, cancer-free BRCA1 mutation-carrying women display lower abundance of circulating CD8+ lymphocytes than the age-matched control group. Thus, our findings support the notion that BRCA1 deficiency in adaptive immunity could contribute to BRCA1-related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.
    Keywords:  Adaptive Immunity; Breast Neoplasms; CD8-Positive T-Lymphocytes
    DOI:  https://doi.org/10.1136/jitc-2022-005852
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