bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–09–22
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
  2. Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control.
  3. Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
  4. Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.
  5. Lipid remodeling in context of cellular senescence.
  6. Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer.
  7. T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer.
  8. Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
  9. 2'-Fucosyllactose attenuates aging-related metabolic disorders through modulating gut microbiome-T cell axis.
  10. New opportunities to overcome T cell dysfunction: the role of transcription factors and how to target them.
  11. Quantifiable blood TCR repertoire components associate with immune aging.
  12. Optimizing CAR-T cell Culture: Differential effects of IL-2, IL-12, and IL-21 on CAR-T cells.
  1. Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]
    Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
    Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.
      Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
    Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2024.08.029
  2. Nat Immunol. 2024 Sep 17.
    Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control.
    Sarah A Weiss, Amy Y Huang, Megan E Fung, Daniela Martinez, Alex C Y Chen, Thomas J LaSalle, Brian C Miller, Christopher D Scharer, Mudra Hegde, Thao H Nguyen, Jared H Rowe, Jossef F Osborn, Dillon G Patterson, Natalia Sifnugel, C Mei-An Nolan, Richard A Davidson, Marc A Schwartz, Alexander P R Bally, Dennis K Neeld, Martin W LaFleur, Jeremy M Boss, John G Doench, W Nicholas Haining, Arlene H Sharpe, Debattama R Sen.
      PD-1 is a key negative regulator of CD8+ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8+ T cells in chronic infection, creating a 'sweet spot' of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8+ T cell dysfunction while avoiding excess immunopathology.
    DOI:  https://doi.org/10.1038/s41590-024-01961-3
  3. Cell Biol Int. 2024 Sep 16.
    Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
    Abhishek Choudhury, Soumya Chatterjee, Shauryabrota Dalui, Pronabesh Ghosh, Altamas Hossain Daptary, Golam Kibria Mollah, Arindam Bhattacharyya.
      Cytotoxic CD8+ T cells plays a pivotal role in the adaptive immune system to protect the organism against infections and cancer. During activation and response, T cells undergo a metabolic reprogramming that involves various metabolic pathways, with a predominant reliance on glycolysis to meet their increased energy demands and enhanced effector response. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Recent reports indicates that exosomes may transfer biologically functional molecules to the recipient cells, thereby facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells. This study sought to enlighten possible involvement of cancer-derived exosomes in CD8 + T cell glucose metabolism and discover a regulated signalome as a mechanism of action. We observed reduction in glucose metabolism due to downregulation of AKT/mTOR signalome in activated CD8 + T cells after cancer derived exosome exposure. In-vivo murine breast tumor studies showed better tumor control and antitumor CD8 + T cell glycolysis and effector response after abrogation of exosome release from breast cancer cells. Summarizing, the present study establishes an immune evasion mechanism of breast cancer cell secreted exosomes that will act as a foundation for future precision cancer therapeutics.
    Keywords:  CD8 + T cells; breast cancer; effector response; exhaustion; exosomes; glycolysis
    DOI:  https://doi.org/10.1002/cbin.12241
  4. EMBO J. 2024 Sep 16.
    Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.
    Romain Vuillefroy de Silly, Laetitia Pericou, Bili Seijo, Isaac Crespo, Melita Irving.
      CD8 + T cells have critical roles in tumor control, but a range of factors in their microenvironment such as low pH can suppress their function. Here, we demonstrate that acidity restricts T-cell expansion mainly through impairing IL-2 responsiveness, lowers cytokine secretion upon re-activation, and reduces the cytolytic capacity of CD8 + T cells expressing low-affinity TCR. We further find decreased mTORC1 signaling activity and c-Myc levels at low pH. Mechanistically, nuclear/cytoplasmic acidification is linked to mTORC1 suppression in a Rheb-, Akt/TSC2/PRAS40-, GATOR1- and Lkb1/AMPK-independent manner, while c-Myc levels drop due to both decreased transcription and higher levels of proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate, and aspartate, as well as elevated proline levels are observed with no apparent impact on mTORC1 signaling or c-Myc levels. Overall, we suggest that, due to the broad impact of acidity on CD8 + T cells, multiple interventions will be required to restore T-cell function unless intracellular pH is effectively controlled.
    Keywords:  Acidity; CD8+ T cell; IL-2; c-Myc; mTOR
    DOI:  https://doi.org/10.1038/s44318-024-00235-w
  5. Biochimie. 2024 Sep 17. pii: S0300-9084(24)00213-X. [Epub ahead of print]
    Lipid remodeling in context of cellular senescence.
    Khaled Tighanimine.
      Cellular senescence is a response that irreversibly arrests stressed cells thus providing a potent tumor suppressor mechanism. In parallel, senescent cells exhibit an immunogenic secretome called SASP (senescence-associated secretory phenotype) that impairs tissue homeostasis and is involved in numerous age-related diseases. Senescence establishment is achieved through the unfolding of a profound transcriptional reprogramming together with morphological changes. These alterations are accompanied by important metabolic adaptations characterized by biosynthetic pathways reshuffling and lipid remodeling. In this mini-review we highlight the intricate links between lipid metabolism and the senescence program and we discuss the potential interventions on lipid pathways that can alleviate the senescence burden.
    Keywords:  SASP; Senescence; cell cycle; lipids
    DOI:  https://doi.org/10.1016/j.biochi.2024.09.003
  6. Cancer Res. 2024 Sep 18.
    Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer.
    Chengying Cui, Haojie Zhang, Congcong Yang, Mingwei Yin, Xinkun Teng, Miaomiao Yang, Dejie Kong, Jinzhi Zhang, Weidong Peng, Zhimin Chu, Jingjing Wang, Yating Sun, Liping Kang, Bin Lyu, Qian Gao, Mingqing Wu, Yongqiang Wang, Yang Li.
      Currently, only 20-40% of cancer patients benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunological landscape during treatment are critical for improving responsiveness to immunotherapy. Here, we identified JNK signaling in cancer-associated fibroblasts (CAFs) as a regulator of the immunosuppressive tumor microenvironment. Single-cell RNA sequencing of bladder cancer treated with a JNK inhibitor revealed enhanced cytotoxicity and effector functions of CD8+ T cells. In untreated tumors, CAFs interacted frequently with CD8+ T cells and mediated their exhaustion. JNK inhibition abrogated the immunosuppression function of CAFs by downregulating the expression of TSLP, thereby restoring CD8+ T cell cytotoxicity. In addition, blockade of CAF-derived TSLP in combination with anti-PD1 treatment promoted tumor elimination by CD8+ T cells in vivo. Collectively, these results indicate that JNK signaling plays an important immunosuppressive role in the tumor microenvironment by promoting expression of TSLP in CAFs and suggest that inhibiting JNK signaling could be a promising immunotherapeutic strategy for cancer treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0940
  7. iScience. 2024 Sep 20. 27(9): 110754
    T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer.
    Kelly Tran, Anita N Kumari, Dinesh Raghu, Daniel R A Cox, Su Kah Goh, Marcos V Perini, Vijayaragavan Muralidharan, Niall C Tebbutt, Andreas Behren, John Mariadason, David S Williams, Lisa A Mielke.
      The presence of precursor to exhausted (Tpex) CD8+ T cells is important to maintain robust immunity following treatment with immune checkpoint inhibition (ICI). Impressive responses to ICI are emerging in patients with stage II-III mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC). We found 64% of dMMR and 15% of mismatch repair-proficient (pMMR) stage III CRCs had a high frequency of tumor infiltrating lymphocytes (TIL-hi). Furthermore, expression of TCF-1 (Tcf7) by CD8+ T cells predicted improved patient prognosis and Tpex cells (CD3+CD8+TCF-1+PD-1+) were abundant within lymphoid aggregates of stage III CRCs. In contrast, CD3+CD8+TCF-1-PD-1+ cells were more abundant at the invasive front and tumor core, while γδ T cells were equally abundant in all tumor areas. Interestingly, no differences in the frequency of Tpex cells were observed between TIL-hi dMMR and TIL-hi pMMR CRCs. Therefore, Tpex cell function and ICI response rates in TIL-hi CRC warrants further investigation.
    Keywords:  Cancer; Components of the immune system; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2024.110754
  8. Nat Cardiovasc Res. 2024 Sep 18.
    Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
    Khanh V Doan, Timothy S Luongo, Thato T Ts'olo, Won Dong Lee, David W Frederick, Sarmistha Mukherjee, Gabriel K Adzika, Caroline E Perry, Ryan B Gaspar, Nicole Walker, Megan C Blair, Nicole Bye, James G Davis, Corey D Holman, Qingwei Chu, Lin Wang, Joshua D Rabinowitz, Daniel P Kelly, Thomas P Cappola, Kenneth B Margulies, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.
    DOI:  https://doi.org/10.1038/s44161-024-00542-9
  9. Aging Cell. 2024 Sep 20. e14343
    2'-Fucosyllactose attenuates aging-related metabolic disorders through modulating gut microbiome-T cell axis.
    Ang Li, Ruixin Kou, Ruishan Wang, Jin Wang, Bowei Zhang, Jingmin Liu, Yaozhong Hu, Shuo Wang.
      Aging-related metabolic disorders seriously affect the lifespan of middle-aged and older people, potentially due to disruptions in the adaptive immune and gut microbial profiles. Dietary intervention offers a promising strategy for maintaining metabolic health. This study aimed to investigate the ameliorative effect of 2'-fucosyllactose (2'-FL) on aging-induced metabolic dysfunction and the underlying mechanisms. The results revealed that 2'-FL significantly relieved aging-related metabolic disorders, including weight gain, lipid deposition, dyslipidemia, glucose intolerance, systemic inflammation, and abnormal hepatic metabolism. Flow cytometry analysis revealed a significant reduction in T cytotoxic (Tc), T helper (Th), and regulatory T (Treg) cells and a significant increase in Th17 cells in aged mice, while 2'-FL relieved the aging-induced proportional changes in Th and Th17 subtypes. The aging intestinal microecology was characterized by higher Th17/Treg ratios, impaired gut barrier function, lower gut bacterial diversity, decreased abundance of beneficial genera including Ligilactobacillus, Colidextribacter, Mucispirillum, and Lachnoclostridium, and increased abundance of harmful bacteria including Turicibacter and Desulfovibrio, which was ameliorated by 2'-FL treatment. These findings highlight that 2'-FL is an ideal dietary prebiotic for improving aging-related metabolic disorders by modulating both the adaptive immune system and the gut microbial profile.
    Keywords:  2'‐Fucosyllactose; T cell; aging; gut microbiota; metabolic dysfunction
    DOI:  https://doi.org/10.1111/acel.14343
  10. Trends Biochem Sci. 2024 Sep 13. pii: S0968-0004(24)00189-0. [Epub ahead of print]
    New opportunities to overcome T cell dysfunction: the role of transcription factors and how to target them.
    Bocheng Wu, Angela N Koehler, Peter M K Westcott.
      Immune checkpoint blockade (ICB) therapies, which block inhibitory receptors on T cells, can be efficacious in reinvigorating dysfunctional T cell responses. However, most cancers do not respond to these therapies and even in those that respond, tumors can acquire resistance. New strategies are needed to rescue and recruit T cell responses across patient populations and disease states. In this review, we define mechanisms of T cell dysfunction, focusing on key transcription factor (TF) networks. We discuss the complex and sometimes contradictory roles of core TFs in both T cell function and dysfunction. Finally, we review strategies to target TFs using small molecule modulators, which represent a challenging but highly promising opportunity to tune the T cell response toward sustained immunity.
    Keywords:  ICB; NR4A; PROTAC degraders; T cell dysfunction; TOX; disordered proteins; immunotherapy; small molecule inhibitor; transcriptional factor
    DOI:  https://doi.org/10.1016/j.tibs.2024.08.002
  11. Nat Commun. 2024 Sep 17. 15(1): 8171
    Quantifiable blood TCR repertoire components associate with immune aging.
    Jing Hu, Mingyao Pan, Brett Reid, Shelley Tworoger, Bo Li.
      T cell senescence alters the homeostasis of distinct T cell populations and results in decayed adaptive immune protection in older individuals, but a link between aging and dynamic T cell clone changes has not been made. Here, using a newly developed computational framework, Repertoire Functional Units (RFU), we investigate over 6500 publicly available TCR repertoire sequencing samples from multiple human cohorts and identify age-associated RFUs consistently across different cohorts. Quantification of RFU reduction with aging reveals accelerated loss under immunosuppressive conditions. Systematic analysis of age-associated RFUs in clinical samples manifests a potential link between these RFUs and improved clinical outcomes, such as lower ICU admission and reduced risk of complications, during acute viral infections. Finally, patients receiving bone marrow transplantation show a secondary expansion of the age-associated clones upon stem cell transfer from younger donors. Together, our results suggest the existence of a 'TCR clock' that could reflect the immune functions in aging populations.
    DOI:  https://doi.org/10.1038/s41467-024-52522-z
  12. Cytokine. 2024 Sep 18. pii: S1043-4666(24)00262-X. [Epub ahead of print]184 156758
    Optimizing CAR-T cell Culture: Differential effects of IL-2, IL-12, and IL-21 on CAR-T cells.
    Mengmeng Zhang, JingJing Kong, Fanxiang Yin, Jianxiang Shi, Jin Li, Zan Qiu, Baohong Yue, Shuya Wang, Nannan Sun, Quande Lin, Liyan Fu, Xiaoqian Wang, Xianlei Sun, Yanxia Gao, Yong Jiang, Rongqun Guo.
       BACKGROUND: Chimeric antigen receptor (CAR)-T therapy has demonstrated sustained clinical remission in numerous hematologic malignancies and has expanded to encompass solid tumors and autoimmune diseases. While progress is being made in establishing optimal culture conditions for CAR-T cells, the identification of the most effective cytokine for promoting their persistence in vitro remains elusive.
    METHODS: Here, we employed scRNA-seq (single-cell RNA sequencing) analysis to investigate the potential alterations in biological processes within CAR-T cells following exposure to cytokines (IL-2, IL-12, and IL-21) and antigens. Transcriptomic changes in diverse CAR-T groups were compared following various treatments, with a focus on epigenetic modifications, metabolic shifts, cellular senescence, and exhaustion.
    RESULTS: Our study reveals that CAR-T cells treated with antigen, IL-2, and IL-12 exhibit signs of exhaustion and senescence, whereas those treated with IL-21 do not display these characteristics. The activities of glycolysis and epigenetic changes were significantly increased by treatments with antigens, IL-2, and IL-12, while IL-21 treatment maintained the oxidative phosphorylation (OXPHOS) of CAR-T cells.
    CONCLUSIONS: Our findings suggest that IL-21 may play a role in preventing senescence and could be utilized in combination with other strategies, such as IL-2 and IL-12, for CAR-T culture.
    Keywords:  CAR-T; Cellular senescence; Epigenetic changes; Exhausted T cells; Metabolic reprogramming; scRNA-seq
    DOI:  https://doi.org/10.1016/j.cyto.2024.156758
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