bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021–05–16
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
  2. Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing.
  3. The emerging role of miRNA in regulating the mTOR signaling pathway in immune and inflammatory responses.
  4. CD8+ T cell metabolism in infection and cancer.
  5. Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells.
  6. Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance.
  7. An aged immune system drives senescence and ageing of solid organs.
  8. Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells.
  9. Hallmarks of T cell aging.
  10. CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria.
  11. SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity.
  12. CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory.
  13. Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments.
  14. Regulatory Role of Zinc in Immune Cell Signaling.
  15. Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint.
  16. De-stressing the T cells in need.
  1. Cell Rep. 2021 May 11. pii: S2211-1247(21)00435-6. [Epub ahead of print]35(6): 109101
    Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
    Nicholas T Crump, Andreas V Hadjinicolaou, Meng Xia, John Walsby-Tickle, Uzi Gileadi, Ji-Li Chen, Mashiko Setshedi, Lars R Olsen, I-Jun Lau, Laura Godfrey, Lynn Quek, Zhanru Yu, Erica Ballabio, Mike B Barnkob, Giorgio Napolitani, Mariolina Salio, Hashem Koohy, Benedikt M Kessler, Stephen Taylor, Paresh Vyas, James S O McCullagh, Thomas A Milne, Vincenzo Cerundolo.
      Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
    Keywords:  ASS1; ATF4; H3K27me3; T cell chromatin; arginine; cancer metabolism; immunometabolism; immunosuppression; metabolic regulation; nutritional stress
    DOI:  https://doi.org/10.1016/j.celrep.2021.109101
  2. Nat Commun. 2021 May 11. 12(1): 2715
    Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing.
    Mariana Borsa, Niculò Barandun, Fabienne Gräbnitz, Isabel Barnstorf, Nicolas S Baumann, Katharina Pallmer, Samira Baumann, Dominique Stark, Miroslav Balaz, Nathalie Oetiker, Franziska Wagen, Christian Wolfrum, Anna Katharina Simon, Nicole Joller, Yves Barral, Roman Spörri, Annette Oxenius.
      Efficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing.
    DOI:  https://doi.org/10.1038/s41467-021-22954-y
  3. Immunol Cell Biol. 2021 May 14.
    The emerging role of miRNA in regulating the mTOR signaling pathway in immune and inflammatory responses.
    Nazanin Nazari, Farzaneh Jafari, Ghasem Ghalamfarsa, Abolghasem Hadinia, Amir Atapour, Majid Ahmadi, Sanam Dolati, Davood Rostamzadeh.
      The mechanistic/mammalian target of rapamycin (mTOR) is considered to be an atypical protein kinase that plays a critical role in integrating different cellular and environmental inputs in the form of growth factors, nutrients, and energy and, subsequently, in regulating different cellular events, including cell metabolism, survival, homeostasis, growth, and cellular differentiation. Immunologically, mTOR is a critical regulator of immune function through integrating numerous signals from the immune microenvironment, which coordinates the functions of immune cells and T cell fate decisions. The crucial role of mTOR in immune responses has been lately even more appreciated. MicroRNAs (miRNAs) are endogenous, small, non-coding single-stranded RNAs that act as molecular regulators involved in multiple processes during immune cells development, homeostasis, activation, and effector polarization. Several studies have recently indicated that a range of miRNAs is involved in regulating the PI3K/AKT/mTOR signaling pathway by targeting multiple components of this signaling pathway and modulating the expression and function of these targets. Current evidence has revealed the interplay between miRNAs and the mTOR pathway circuits in various immune cell-types. The expression of individual miRNA can affect the function of mTOR signaling to determine the cell fate decisions in immune responses through coordinating immune signaling and cell metabolism. Dysregulation of the mTOR pathway/miRNAs crosstalk has been reported in cancers and various immune-related diseases. Thus, dysregulated miRNAs expression profiles could influence the mTOR pathway, resulting in the promotion of aberrant immunity. This review summarizes the latest information regarding the reciprocal role of the mTOR signaling pathway and miRNAs in orchestrating immune responses.
    Keywords:  AKT; Immune response; PTEN; mTOR signaling; miRNAs
    DOI:  https://doi.org/10.1111/imcb.12477
  4. Nat Rev Immunol. 2021 May 12.
    CD8+ T cell metabolism in infection and cancer.
    Miguel Reina-Campos, Nicole E Scharping, Ananda W Goldrath.
      Cytotoxic CD8+ T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8+ T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8+ T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8+ T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8+ T cell-mediated immunity. Defining the metabolic adaptations of CD8+ T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8+ T cell programmes and discuss how metabolism is integrated with CD8+ T cell differentiation and function and determined by environmental cues.
    DOI:  https://doi.org/10.1038/s41577-021-00537-8
  5. Cell Rep. 2021 May 11. pii: S2211-1247(21)00459-9. [Epub ahead of print]35(6): 109120
    Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells.
    Laura M McLane, Shin Foong Ngiow, Zeyu Chen, John Attanasio, Sasikanth Manne, Gordon Ruthel, Jennifer E Wu, Ryan P Staupe, Wei Xu, Ravi K Amaravadi, Xiaowei Xu, Giorgos C Karakousis, Tara C Mitchell, Lynn M Schuchter, Alexander C Huang, Bruce D Freedman, Michael R Betts, E John Wherry.
      The transcription factors T-bet and Eomesodermin (Eomes) regulate CD8 T cell exhaustion through undefined mechanisms. Here, we show that the subcellular localization of T-bet and Eomes dictate their regulatory activity in exhausted T cells (TEXs). TEXs had a higher ratio of nuclear Eomes:T-bet than memory T cells (TMEMs) during chronic lymphocytic choriomeningitis virus (LCMV) infection in preclinical cancer models and in human tumors. Biochemically, T-bet and Eomes compete for the same DNA sequences, including the Pdcd1 T-box. High nuclear T-bet strongly represses Pdcd1 transcription in TMEM, whereas low nuclear T-bet in TEX leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in TEXs increases nuclear T-bet, restoring stronger repression of Pdcd1, and driving T-bet-associated gene expression programs of chemotaxis, homing, and activation. These data identify a mechanism whereby the T-bet-Eomes axis regulates exhaustion through their nuclear localization, providing insights into how these transcription factors regulate TEX biology.
    Keywords:  Eomes; PD-1; T cell exhaustion; T-bet; cancer; checkpoint blockade; chronic infection; exhausted T cell reinvigoration
    DOI:  https://doi.org/10.1016/j.celrep.2021.109120
  6. Nat Commun. 2021 May 13. 12(1): 2782
    Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance.
    Mayura V Wagle, Stephin J Vervoort, Madison J Kelly, Willem Van Der Byl, Timothy J Peters, Ben P Martin, Luciano G Martelotto, Simone Nüssing, Kelly M Ramsbottom, James R Torpy, Deborah Knight, Sinead Reading, Kevin Thia, Lisa A Miosge, Debbie R Howard, Renee Gloury, Sarah S Gabriel, Daniel T Utzschneider, Jane Oliaro, Jonathan D Powell, Fabio Luciani, Joseph A Trapani, Ricky W Johnstone, Axel Kallies, Christopher C Goodnow, Ian A Parish.
      Chronic stimulation of CD8+ T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells.
    DOI:  https://doi.org/10.1038/s41467-021-23044-9
  7. Nature. 2021 May 12.
    An aged immune system drives senescence and ageing of solid organs.
    Matthew J Yousefzadeh, Rafael R Flores, Yi Zhu, Zoe C Schmiechen, Robert W Brooks, Christy E Trussoni, Yuxiang Cui, Luise Angelini, Kyoo-A Lee, Sara J McGowan, Adam L Burrack, Dong Wang, Qing Dong, Aiping Lu, Tokio Sano, Ryan D O'Kelly, Collin A McGuckian, Jonathan I Kato, Michael P Bank, Erin A Wade, Smitha P S Pillai, Jenna Klug, Warren C Ladiges, Christin E Burd, Sara E Lewis, Nicholas F LaRusso, Nam V Vo, Yinsheng Wang, Eric E Kelley, Johnny Huard, Ingunn M Stromnes, Paul D Robbins, Laura J Niedernhofer.
      Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
    DOI:  https://doi.org/10.1038/s41586-021-03547-7
  8. Nat Commun. 2021 May 11. 12(1): 2665
    Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells.
    Xuan Sun, Benjamin Cao, Marina Naval-Sanchez, Tony Pham, Yu Bo Yang Sun, Brenda Williams, Shen Y Heazlewood, Nikita Deshpande, Jinhua Li, Felix Kraus, James Rae, Quan Nguyen, Hamed Yari, Jan Schröder, Chad K Heazlewood, Madeline Fulton, Jessica Hatwell-Humble, Kaustav Das Gupta, Ronan Kapetanovic, Xiaoli Chen, Matthew J Sweet, Robert G Parton, Michael T Ryan, Jose M Polo, Christian M Nefzger, Susan K Nilsson.
      With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.
    DOI:  https://doi.org/10.1038/s41467-021-22863-0
  9. Nat Immunol. 2021 May 13.
    Hallmarks of T cell aging.
    Maria Mittelbrunn, Guido Kroemer.
      The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4+ T cell-intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive-memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.
    DOI:  https://doi.org/10.1038/s41590-021-00927-z
  10. J Allergy Clin Immunol. 2021 May 06. pii: S0091-6749(21)00555-8. [Epub ahead of print]
    CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria.
    Luís Almeida, Ayesha Dhillon-LaBrooy, Guilhermina Carriche, Luciana Berod, Tim Sparwasser.
      The progression through different steps of T-cell development, activation, and effector function is tightly bound to specific cellular metabolic processes. Previous studies established that T-effector cells have a metabolic bias toward aerobic glycolysis, whereas naive and regulatory T cells mainly rely on oxidative phosphorylation. More recently, the field of immunometabolism has drifted away from the notion that mitochondrial metabolism holds little importance in T-cell activation and function. Of note, T cells possess metabolic promiscuity, which allows them to adapt their nutritional requirements according to the tissue environment. Altogether, the integration of these metabolic pathways culminates in the generation of not only energy but also intermediates, which can regulate epigenetic programs, leading to changes in T-cell fate. In this review, we discuss the recent literature on how glycolysis, amino acid catabolism, and fatty acid oxidation work together with the tricarboxylic acid cycle in the mitochondrion. We also emphasize the importance of the electron transport chain for T-cell immunity. We also discuss novel findings highlighting the role of key enzymes, accessory pathways, and posttranslational protein modifications that distinctively regulate T-cell function and might represent prominent candidates for therapeutic purposes.
    Keywords:  CD4; T cell; antibiotics; arginine; fatty acid oxidation; immunometabolism; metabolism; mitochondria; polyamine
    DOI:  https://doi.org/10.1016/j.jaci.2021.03.033
  11. Science. 2021 May 14. pii: eaba4220. [Epub ahead of print]372(6543):
    SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity.
    Tao Yue, Xiaoming Zhan, Duanwu Zhang, Ruchi Jain, Kuan-Wen Wang, Jin Huk Choi, Takuma Misawa, Lijing Su, Jiexia Quan, Sara Hildebrand, Darui Xu, Xiaohong Li, Emre Turer, Lei Sun, Eva Marie Y Moresco, Bruce Beutler.
      Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell-specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2's mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.
    DOI:  https://doi.org/10.1126/science.aba4220
  12. Cancer Discov. 2021 May 14. pii: candisc.1554.2020. [Epub ahead of print]
    CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory.
    Emily J Lelliott, Isabella Y Kong, Magnus Zethoven, Kelly M Ramsbottom, Luciano G Martelotto, Deborah Meyran, Joe Jiang Zhu, Matteo Costacurta, Laura Kirby, Jarrod J Sandow, Lydia Lim, Pilar M Dominguez, Izabela Todorovski, Nicole M Haynes, Paul A Beavis, Paul J Neeson, Edwin D Hawkins, Grant A McArthur, Ian A Parish, Ricky W Johnstone, Jane Oliaro, Karen E Sheppard, Conor J Kearney, Stephin J Vervoort.
      Pharmacological inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1554
  13. Nat Commun. 2021 May 14. 12(1): 2815
    Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments.
    Erdem D Tabdanov, Nelson J Rodríguez-Merced, Alexander X Cartagena-Rivera, Vikram V Puram, Mackenzie K Callaway, Ethan A Ensminger, Emily J Pomeroy, Kenta Yamamoto, Walker S Lahr, Beau R Webber, Branden S Moriarity, Alexander S Zhovmer, Paolo P Provenzano.
      Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.
    DOI:  https://doi.org/10.1038/s41467-021-22985-5
  14. Mol Cells. 2021 May 14.
    Regulatory Role of Zinc in Immune Cell Signaling.
    Bonah Kim, Won-Woo Lee.
      Zinc is an essential micronutrient with crucial roles in multiple facets of biological processes. Dysregulated zinc homeostasis impairs overall immune function and resultantly increases susceptibility to infection. Clinically, zinc supplementation is practiced for treatment of several infectious diseases, such as diarrhea and malaria. Recent focus on zinc as a beneficial element for immune system support has resulted in investigation of the immunomodulatory roles of zinc in a variety of immune cells. Besides its classical role as a cofactor that regulates the structural function of thousands of proteins, accumulating evidence suggests that zinc also acts, in a manner similar to calcium, as an ionic regulator of immune responses via participation as an intracellular messenger in signaling pathways. In this review, we focus on the role of zinc as a signaling molecule in major pathways such as those downstream of Toll-like receptors-, T cell receptor-, and cytokine-mediated signal transduction that regulate the activity and function of monocytes/macrophages and T cells, principal players in the innate and adaptive immune systems.
    Keywords:  T cell receptor; T cells; Toll-like receptors; monocytes/macrophages; phosphatase; signaling pathways; zinc; zinc transporter
    DOI:  https://doi.org/10.14348/molcells.2021.0061
  15. Nat Commun. 2021 May 14. 12(1): 2814
    Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint.
    Nathalie M Schmidt, Peter A C Wing, Mariana O Diniz, Laura J Pallett, Leo Swadling, James M Harris, Alice R Burton, Anna Jeffery-Smith, Nekisa Zakeri, Oliver E Amin, Stephanie Kucykowicz, Mirjam H Heemskerk, Brian Davidson, Tim Meyer, Joe Grove, Hans J Stauss, Ines Pineda-Torra, Clare Jolly, Elizabeth C Jury, Jane A McKeating, Mala K Maini.
      Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.
    DOI:  https://doi.org/10.1038/s41467-021-22967-7
  16. Science. 2021 May 14. 372(6543): 683-684
    De-stressing the T cells in need.
    Zhangli Su, Anindya Dutta.
      
    DOI:  https://doi.org/10.1126/science.abi7265
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