bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–11–13
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Role of CAR T Cell Metabolism for Therapeutic Efficacy.
  2. T cell aging as a risk factor for autoimmunity.
  3. BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion.
  4. Improving antitumor T cells.
  5. Enhanced T cell effector activity by targeting the Mediator kinase module.
  6. Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy.
  7. Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells.
  8. Gut Microbiota and Tumor Immune Escape: A New Perspective for Improving Tumor Immunotherapy.
  9. Regulation of Cyclooxygenase-2 Expression in Human T Cells by Glucocorticoid Receptor-Mediated Transrepression of Nuclear Factor of Activated T Cells.
  10. Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders.
  11. Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection.
  12. Sirt3 deficiency accelerates ovarian senescence without affecting spermatogenesis in aging mice.
  13. Gut microbiome and metabolome analyses reveal the protective effect of special high-docosahexaenoic acid tuna oil on d-galactose-induced aging in mice.
  1. Cancers (Basel). 2022 Nov 04. pii: 5442. [Epub ahead of print]14(21):
    Role of CAR T Cell Metabolism for Therapeutic Efficacy.
    Judit Rial Saborido, Simon Völkl, Michael Aigner, Andreas Mackensen, Dimitrios Mougiakakos.
      Chimeric antigen receptor (CAR) T cells hold enormous potential. However, a substantial proportion of patients receiving CAR T cells will not reach long-term full remission. One of the causes lies in their premature exhaustion, which also includes a metabolic anergy of adoptively transferred CAR T cells. T cell phenotypes that have been shown to be particularly well suited for CAR T cell therapy display certain metabolic characteristics; whereas T-stem cell memory (TSCM) cells, characterized by self-renewal and persistence, preferentially meet their energetic demands through oxidative phosphorylation (OXPHOS), effector T cells (TEFF) rely on glycolysis to support their cytotoxic function. Various parameters of CAR T cell design and manufacture co-determine the metabolic profile of the final cell product. A co-stimulatory 4-1BB domain promotes OXPHOS and formation of central memory T cells (TCM), while T cells expressing CARs with CD28 domains predominantly utilize aerobic glycolysis and differentiate into effector memory T cells (TEM). Therefore, modification of CAR co-stimulation represents one of the many strategies currently being investigated for improving CAR T cells' metabolic fitness and survivability within a hostile tumor microenvironment (TME). In this review, we will focus on the role of CAR T cell metabolism in therapeutic efficacy together with potential targets of intervention.
    Keywords:  CAR T cells; bioenergetics; immune escape; immunometabolism; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14215442
  2. J Autoimmun. 2022 Nov 07. pii: S0896-8411(22)00155-X. [Epub ahead of print] 102947
    T cell aging as a risk factor for autoimmunity.
    Qingxiang Liu, Yanyan Zheng, Jorg J Goronzy, Cornelia M Weyand.
      Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.
    Keywords:  Autoimmune disease; Giant cell arteritis; Immune aging; Inflammaging; Rheumatoid arthritis; T cell aging
    DOI:  https://doi.org/10.1016/j.jaut.2022.102947
  3. Sci Transl Med. 2022 Nov 09. 14(670): eabn7336
    BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion.
    In-Young Jung, Vivek Narayan, Sierra McDonald, Andrew J Rech, Robert Bartoszek, Gwanui Hong, Megan M Davis, Jun Xu, Alina C Boesteanu, Julie S Barber-Rotenberg, Gabriela Plesa, Simon F Lacey, Julie K Jadlowsky, Donald L Siegel, Dana M Hammill, Park F Cho-Park, Shelley L Berger, Naomi B Haas, Joseph A Fraietta.
      Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.
    DOI:  https://doi.org/10.1126/scitranslmed.abn7336
  4. Science. 2022 Nov 11. 378(6620): 598
    Improving antitumor T cells.
    Caitlin C Zebley, Ben Youngblood.
      Disrupting cell cycle regulators can overcome anticancer T cell dysfunction.
    DOI:  https://doi.org/10.1126/science.adf0546
  5. Science. 2022 Nov 11. 378(6620): eabn5647
    Enhanced T cell effector activity by targeting the Mediator kinase module.
    Katherine A Freitas, Julia A Belk, Elena Sotillo, Patrick J Quinn, Maria C Ramello, Meena Malipatlolla, Bence Daniel, Katalin Sandor, Dorota Klysz, Jeremy Bjelajac, Peng Xu, Kylie A Burdsall, Victor Tieu, Vandon T Duong, Micah G Donovan, Evan W Weber, Howard Y Chang, Robbie G Majzner, Joaquin M Espinosa, Ansuman T Satpathy, Crystal L Mackall.
      T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC, components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor-engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12-deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers-most notably for STAT and AP-1 transcription factors-and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.
    DOI:  https://doi.org/10.1126/science.abn5647
  6. Immunity. 2022 Nov 08. pii: S1074-7613(22)00508-8. [Epub ahead of print]55(11): 2059-2073.e8
    Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy.
    Dominic Denk, Valentina Petrocelli, Claire Conche, Moritz Drachsler, Paul K Ziegler, Angela Braun, Alena Kress, Adele M Nicolas, Kathleen Mohs, Christoph Becker, Markus F Neurath, Henner F Farin, Christian J Buchholz, Pénélope A Andreux, Chris Rinsch, Florian R Greten.
      T memory stem cells (TSCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. TSCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced TSCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to TSCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.
    Keywords:  T(SCM); anti-tumor immunity; mitophagy
    DOI:  https://doi.org/10.1016/j.immuni.2022.09.014
  7. Cells. 2022 Nov 03. pii: 3489. [Epub ahead of print]11(21):
    Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells.
    Lea Katharina Picard, Elisabeth Littwitz-Salomon, Herbert Waldmann, Carsten Watzl.
      Tumor cells often have very high energy demands. Inhibition of glucose uptake is therefore a possible approach to limit the proliferation and survival of transformed cells. However, immune cells also require energy to initiate and to maintain anti-tumor immune reactions. Here, we investigate the effect of Glutor, an inhibitor of glucose transporters, on the function of human Natural Killer (NK) cells, which are important for the immunosurveillance of cancer. Glutor treatment effectively inhibits glycolysis in NK cells. However, acute treatment with the inhibitor has no effect on NK cell effector functions. Prolonged inhibition of glucose uptake by Glutor prevents the proliferation of NK cells, increases their pro-inflammatory regulatory function and reduces the stimulation-dependent production of IFN-γ. Interestingly, even after prolonged Glutor treatment NK cell cytotoxicity and serial killing activity were still intact, demonstrating that cytotoxic NK cell effector functions are remarkably robust against metabolic disturbances.
    Keywords:  cytokines; degranulation; glucose transporter; metabolism; natural killer cells
    DOI:  https://doi.org/10.3390/cells11213489
  8. Cancers (Basel). 2022 Oct 28. pii: 5317. [Epub ahead of print]14(21):
    Gut Microbiota and Tumor Immune Escape: A New Perspective for Improving Tumor Immunotherapy.
    Yunbo He, Jinliang Huang, Qiaorong Li, Weiping Xia, Chunyu Zhang, Zhi Liu, Jiatong Xiao, Zhenglin Yi, Hao Deng, Zicheng Xiao, Jiao Hu, Huihuang Li, Xiongbing Zu, Chao Quan, Jinbo Chen.
      The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment.
    Keywords:  gut microbiota; immune checkpoint inhibitor; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14215317
  9. Int J Mol Sci. 2022 Oct 31. pii: 13275. [Epub ahead of print]23(21):
    Regulation of Cyclooxygenase-2 Expression in Human T Cells by Glucocorticoid Receptor-Mediated Transrepression of Nuclear Factor of Activated T Cells.
    Cristina Cacheiro-Llaguno, Elena Hernández-Subirá, Manuel D Díaz-Muñoz, Manuel Fresno, Juan M Serrador, Miguel A Íñiguez.
      Cyclooxygenase (COX) is the key enzyme in prostanoid synthesis from arachidonic acid (AA). Two isoforms, named COX-1 and COX-2, are expressed in mammalian tissues. The expression of COX-2 isoform is induced by several stimuli including cytokines and mitogens, and this induction is inhibited by glucocorticoids (GCs). We have previously shown that the transcriptional induction of COX-2 occurs early after T cell receptor (TCR) triggering, suggesting functional implications of this enzyme in T cell activation. Here, we show that dexamethasone (Dex) inhibits nuclear factor of activated T cells (NFAT)-mediated COX-2 transcriptional induction upon T cell activation. This effect is dependent on the presence of the GC receptor (GR), but independent of a functional DNA binding domain, as the activation-deficient GRLS7 mutant was as effective as the wild-type GR in the repression of NFAT-dependent transcription. Dex treatment did not disturb NFAT dephosphorylation, but interfered with activation mediated by the N-terminal transactivation domain (TAD) of NFAT, thus pointing to a negative cross-talk between GR and NFAT at the nuclear level. These results unveil the ability of GCs to interfere with NFAT activation and the induction of pro-inflammatory genes such as COX-2, and explain some of their immunomodulatory properties in activated human T cells.
    Keywords:  Cyclooxygenase-2; NFAT; T cells; glucocorticoid receptor; glucocorticoids; transrepression
    DOI:  https://doi.org/10.3390/ijms232113275
  10. Front Nutr. 2022 ;9 1011732
    Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders.
    Renan Oliveira Corrêa, Pollyana Ribeiro Castro, René Moser, Caroline Marcantonio Ferreira, Valerie F J Quesniaux, Marco Aurélio Ramirez Vinolo, Bernhard Ryffel.
      Short-chain fatty acids (SCFAs) are metabolites released by bacterial components of the microbiota. These molecules have a wide range of effects in the microbiota itself, but also in host cells in which they are known for contributing to the regulation of cell metabolism, barrier function, and immunological responses. Recent studies indicate that these molecules are important players in the gut-lung axis and highlight the possibility of using strategies that alter their intestinal production to prevent or treat distinct lung inflammatory diseases. Here, we review the effects of the SCFA butyrate and its derivatives in vitro and in vivo on murine models of respiratory disorders, besides discussing the potential therapeutic use of butyrate and the other SCFAs in lung diseases.
    Keywords:  butyrate; inflammation; lung-gut axis; pulmonary disorders; short-chain fatty acids (SCFA)
    DOI:  https://doi.org/10.3389/fnut.2022.1011732
  11. Nat Commun. 2022 Nov 09. 13(1): 6759
    Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection.
    Judy Chen, Jane C Deng, Rachel L Zemans, Karim Bahmed, Beata Kosmider, Min Zhang, Marc Peters-Golden, Daniel R Goldstein.
      Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E2 (PGE2), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE2 within the aged lung. PGE2 impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE2 receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults.
    DOI:  https://doi.org/10.1038/s41467-022-34593-y
  12. Free Radic Biol Med. 2022 Nov 03. pii: S0891-5849(22)00962-5. [Epub ahead of print]
    Sirt3 deficiency accelerates ovarian senescence without affecting spermatogenesis in aging mice.
    Jing Zhu, Qingling Yang, Hui Li, Yujiao Wang, Yuqing Jiang, Huan Wang, Luping Cong, Jianmin Xu, Zhaoyang Shen, Wenhui Chen, Xinxin Zeng, Mengchen Wang, Min Lei, Yingpu Sun.
      Sirtuin-3 (SIRT3), the main deacetylase in the mitochondria, maintains cellular energy metabolism and redox balance by deacetylating mitochondrial proteins in a NAD+-dependent manner. Growing evidence indicates that decreased Sirt3 expression is involved in various age-related maladies. However, the role of Sirt3 in ovarian and testicular senescence remains unclear. In this study, we observed that sirt3 expression showed age-dependent decreases in the ovary but not the testis. We generated Sirt3 null mice via CRISPR/Cas9-mediated genome editing. We observed that Sirt3 deletion accelerated ovarian aging, as shown by a decrease in offspring sizes, the follicle reserve and oocytes markers (Bmp15 and Gdf9) as well as increased expression of aging and inflammation-related genes (p16, p21, Il-1α, and Il-1β). Sirt3 deficiency led to an accumulation of superoxide and disruption of spindle assembly accompanied by mitochondrial dysfunction (uneven mitochondria distribution, decreased mitochondrial potential as well as reduced mitochondrial DNA content) in aging oocytes. Meanwhile, in ovaries of Sirt3 null mice, the impaired mitochondrial functions were shown by decreases in mitochondrial respiratory complexes, along with lower levels of mitochondrial fusion (OPA1, MFN2) and fission (DRP1, FIS1) proteins. er levels of mitochondrial fusion (OPA1, MFN2) and fission (DRP1, FIS1) proteins. Interestingly, Sirt3-/- male mice exhibited no changes on the testicular histology, serum testosterone levels, germ-cell proliferation, and differentiation of spermatogonia. Meiotic prophase I spermatocytes were also normal. Levels of superoxide, mitochondrial potential as well as expression of mitochondrially-encoded genes were unaltered in Sirt3-/- testes. Collectively, the results indicated that SIRT3 plays a critical role in maintaining the ovarian follicle reserve and oocyte quality in aging mice, suggesting its important role in controlling ovarian senescence.
    Keywords:  Mitochondria; Oocyte; Ovary aging; SIRT3; Spermatogenesis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.10.324
  13. Food Sci Nutr. 2022 Nov;10(11): 3814-3827
    Gut microbiome and metabolome analyses reveal the protective effect of special high-docosahexaenoic acid tuna oil on d-galactose-induced aging in mice.
    Jing Zhang, Congmin Yi, Jiaojiao Han, Tinghong Ming, Jun Zhou, Chenyang Lu, Ye Li, Xiurong Su.
      Aging is closely related to altered gut function and its microbiome composition. To elucidate the mechanisms involved in the preventive effect of special high-docosahexaenoic acid tuna oil (HDTO) on senescence, the effects of different doses of HDTO on the gut microbiome and metabolome of d-galactose-induced aging mice were studied. Deferribacteres and Tenericutes and uridine might be used as indicator bacteria and characteristic metabolites to identify aging, respectively. HDTO markedly improved the impaired memory and antioxidant abilities induced by d-galactose. At the phylum level, the abundance of Firmicutes and Tenericutes was significantly increased upon d-galactose induction, while that of Bacteroidetes, Proteobacteria, and Deferribacteres was significantly decreased. At the genus level, the variation mainly presented as an increase in the abundance of the Firmicutes genera Ligilactobacillus, Lactobacillus, and Erysipelothrix, the decrease in the abundance of the Bacteroidetes genera Bacteroides and Alistipes, the Firmicutes genus Dielma, and the Deferribacteres genus Mucispirillum. HDTO supplementation reversed the alterations in the intestinal flora by promoting the proliferation of beneficial flora during the aging process; the metabolic pathways, such as glycine-serine-threonine metabolism, valine-leucine-isoleucine biosynthesis, and some metabolic pathways involved in uridine, were also partially restored. Furthermore, the correlation analysis illustrated an obvious correlation between gut microbiota, its metabolites, and aging-related indices. Moreover, it is worth noting that the metabolic regulation by dietary intervention varied with different HDTO doses and did not present a simple additive effect; indeed, each dose showed a unique modulation mechanism.
    Keywords:  aging; gut microbiome; metabolome; protective effect; special high‐DHA tuna oil
    DOI:  https://doi.org/10.1002/fsn3.2978
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