bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024‒03‒10
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment.
  2. Immunometabolic Maladaptations to the Tumor Microenvironment.
  3. Supercharging cancer-fighting T cells with lithium carbonate.
  4. CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.
  5. The role of Bach2 in regulating CD8 + T cell development and function.
  6. Beyond T cell exhaustion: TIM-3 regulation of myeloid cells.
  7. CD38-RyR2 axis-mediated signaling impedes CD8+ T cell response to anti-PD1 therapy in cancer.
  8. Sustained AhR activity programs memory fate of early effector CD8+ T cells.
  9. Urolithin A Hijacks ERK1/2-ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity.
  10. Endoplasmic reticulum stress in T cell-mediated diseases.
  11. LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
  12. How calorie restriction slows aging: an epigenetic perspective.
  13. Immune aging in annual killifish.
  1. Cell Rep. 2024 Mar 05. pii: S2211-1247(24)00226-2. [Epub ahead of print]43(3): 113898
    NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment.
    Tanakorn Srirat, Taeko Hayakawa, Setsuko Mise-Omata, Kensuke Nakagawara, Makoto Ando, Shigeyuki Shichino, Minako Ito, Akihiko Yoshimura.
      T cell exhaustion impairs tumor immunity and contributes to resistance against immune checkpoint inhibitors. The nuclear receptor subfamily 4 group A (NR4a) family of nuclear receptors plays a crucial role in driving T cell exhaustion. In this study, we observe that NR4a1 and NR4a2 deficiency in CD8+ tumor-infiltrating lymphocytes (TILs) results in potent tumor eradication and exhibits not only reduced exhaustion characteristics but also an increase in the precursors/progenitors of exhausted T (Pre-Tex) cell fraction. Serial transfers of NR4a1-/-NR4a2-/-CD8+ TILs into tumor-bearing mice result in the expansion of TCF1+ (Tcf7+) stem-like Pre-Tex cells, whereas wild-type TILs are depleted upon secondary transfer. NR4a1/2-deficient CD8+ T cells express higher levels of stemness/memory-related genes and illustrate potent mitochondrial oxidative phosphorylation. Collectively, these findings suggest that inhibiting NR4a in tumors represents a potent immuno-oncotherapy strategy by increasing stem-like Pre-Tex cells and reducing exhaustion of CD8+ T cells.
    Keywords:  CP: Cancer; CP: Immunology; NR4a; T cell exhaustion; TCF1; memory T cell; mitochondria; stemness; tumor immunity
    DOI:  https://doi.org/10.1016/j.celrep.2024.113898
  2. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]
    Immunometabolic Maladaptations to the Tumor Microenvironment.
    Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.
      Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041547
  3. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00052-4. [Epub ahead of print]36(3): 463-465
    Supercharging cancer-fighting T cells with lithium carbonate.
    Yue Xu, Kaili Ma, Lianjun Zhang, Guideng Li.
      Lactate influences the behavior of various immune cell types. In a recent Nature Immunology study, Ma et al. revealed that lithium carbonate induces monocarboxylate transporter 1 translocation to mitochondria, enhancing cytoplasmic lactate transport into the mitochondria and increasing lactate mitochondrial metabolism, thereby promoting T cell effector function.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.006
  4. J Clin Invest. 2024 Mar 05. pii: e170071. [Epub ahead of print]
    CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.
    Siqi Chen, Jie Fan, Ping Xie, Jihae Ahn, Michelle Fernandez, Leah K Billingham, Jason Miska, Jennifer D Wu, Derek A Wainwright, Deyu Fang, Jeffrey A Sosman, Yong Wan, Yi Zhang, Navdeep S Chandel, Bin Zhang.
      Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT). Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH-GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.
    Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells
    DOI:  https://doi.org/10.1172/JCI170071
  5. Cell Commun Signal. 2024 Mar 08. 22(1): 169
    The role of Bach2 in regulating CD8 + T cell development and function.
    Xinyu Weng, Min Zheng, Yanning Liu, Guohua Lou.
      Bach2 was initially discovered in B cells, where it was revealed to control the transcription involved in cell differentiation. Bach2 is intimately connected to CD8 + T lymphocytes in various differentiation states and subsets according to recent findings. Bach2 can regulate primitive T cells, stimulate the development and differentiation of memory CD8 + T cells, inhibit the differentiation of effector CD8 + T cells, and play a significant role in the exhaustion of CD8 + T cells. The appearance and development of diseases are tightly linked to irregular CD8 + T cell differentiation and function. Accordingly, Bach2 offers novel approaches and possible targets for the clinical treatment of associated disorders based on research on these pathways. Here, we summarize the role of Bach2 in the function and differentiation of CD8 + T cells and its potential clinical applications.
    Keywords:  Bach2; CD8; Immune diseases; Lymphocytes
    DOI:  https://doi.org/10.1186/s12964-024-01551-8
  6. Sci Immunol. 2024 Mar 08. 9(93): eadf2223
    Beyond T cell exhaustion: TIM-3 regulation of myeloid cells.
    Karen O Dixon, Gonzalo Fernandez Lahore, Vijay K Kuchroo.
      T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an important immune checkpoint molecule initially identified as a marker of IFN-γ-producing CD4+ and CD8+ T cells. Since then, our understanding of its role in immune responses has significantly expanded. Here, we review emerging evidence demonstrating unexpected roles for TIM-3 as a key regulator of myeloid cell function, in addition to recent work establishing TIM-3 as a delineator of terminal T cell exhaustion, thereby positioning TIM-3 at the interface between fatigued immune responses and reinvigoration. We share our perspective on the antagonism between TIM-3 and T cell stemness, discussing both cell-intrinsic and cell-extrinsic mechanisms underlying this relationship. Looking forward, we discuss approaches to decipher the underlying mechanisms by which TIM-3 regulates stemness, which has remarkable potential for the treatment of cancer, autoimmunity, and autoinflammation.
    DOI:  https://doi.org/10.1126/sciimmunol.adf2223
  7. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2315989121
    CD38-RyR2 axis-mediated signaling impedes CD8+ T cell response to anti-PD1 therapy in cancer.
    Anwesha Kar, Puspendu Ghosh, Anupam Gautam, Snehanshu Chowdhury, Debashree Basak, Ishita Sarkar, Arpita Bhoumik, Shubhrajit Barman, Paramita Chakraborty, Asima Mukhopadhyay, Shikhar Mehrotra, Senthil Kumar Ganesan, Sandip Paul, Shilpak Chatterjee.
      PD1 blockade therapy, harnessing the cytotoxic potential of CD8+ T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8+ T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8+ T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8+ T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8+ T cells, revealed that CD38-expressing CD8+ T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8+ T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8+ T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8+ T cells elevated intracellular Ca2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8+ T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.
    Keywords:  CD38; T cell exhaustion; anti-PD1 resistance
    DOI:  https://doi.org/10.1073/pnas.2315989121
  8. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2317658121
    Sustained AhR activity programs memory fate of early effector CD8+ T cells.
    Huafeng Zhang, Zhuoshun Yang, Wu Yuan, Jincheng Liu, Xiao Luo, Qian Zhang, Yonggang Li, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.
      Identification of mechanisms that program early effector T cells to either terminal effector T (Teff) or memory T (Tm) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early Teff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8+ Teff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8+ T cells up-regulate HIF-1α to compete with AhR for HIF-1β, leading to the loss of AhR activity in HIF-1αhigh short-lived effector cells, but sustained in HIF-1αlow memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8+ MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how Teff cells are regulated to differentiate into memory cells.
    Keywords:  CD8+ memory T cells; HIF-1α; aryl hydrocarbon receptor; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2317658121
  9. Adv Sci (Weinh). 2024 Mar 06. e2310065
    Urolithin A Hijacks ERK1/2-ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity.
    Shuaiya Ma, Qi Wu, Wenxian Wu, Ye Tian, Jie Zhang, Chaojia Chen, Xue Sheng, Fangcheng Zhao, Lu Ding, Taixia Wang, Laixi Zhao, Yuying Xie, Yongxiang Wang, Xuetian Yue, Zhuanchang Wu, Jian Wei, Kun Zhang, Xiaohong Liang, Lifen Gao, Hongyan Wang, Guihua Wang, Chunyang Li, Chunhong Ma.
      According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell-mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA-mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA-ERK1/2-ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA-treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.
    Keywords:  CAR T cells; CD8+ cytotoxic T cells; ERK1/2; Urolithin A (UA); autophagy
    DOI:  https://doi.org/10.1002/advs.202310065
  10. Scand J Immunol. 2023 Sep;98(3): e13307
    Endoplasmic reticulum stress in T cell-mediated diseases.
    Shaodan Chen, Qiulei Wang, Hui Wang, Sheng Xia.
      T cells synthesize a large number of proteins during their development, activation, and differentiation. The build-up of misfolded and unfolded proteins in the endoplasmic reticulum, however, causes endoplasmic reticulum (ER) stress. Thus, T cells can maintain ER homeostasis via endoplasmic reticulum-associated degradation, unfolded protein response, and autophagy. In T cell-mediated diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes and vitiligo, ER stress caused by changes in the internal microenvironment can cause disease progression by affecting T cell homeostasis. This review discusses ER stress in T cell formation, activation, differentiation, and T cell-mediated illnesses, and may offer new perspectives on the involvement of T cells in autoimmune disorders and cancer.
    Keywords:  ER stress; ERAD; T cell; T cell‐mediated disease; UPR; autophagy
    DOI:  https://doi.org/10.1111/sji.13307
  11. Cell Rep. 2024 Mar 05. pii: S2211-1247(24)00227-4. [Epub ahead of print]43(3): 113899
    LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
    Taruna Pandey, Bingying Wang, Changnan Wang, Jenny Zu, Huichao Deng, Kang Shen, Goncalo Dias do Vale, Jeffrey G McDonald, Dengke K Ma.
      Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
    Keywords:  CP: Metabolism; CP: Molecular biology; Caenorhabditis elegans; IIS-mTOR; INS-7; LPD-3; aging; hexaceramide; hyperfunction; mitochondrial pathway; molecular damages; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2024.113899
  12. J Mol Med (Berl). 2024 Mar 08.
    How calorie restriction slows aging: an epigenetic perspective.
    Gyeong Min Lim, Nagarajan Maharajan, Gwang-Won Cho.
      Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA methylation are associated with abnormal gene expression, leading to diseases and genomic instability. Modulation of these epigenetic changes is crucial for preserving genomic integrity and controlling cellular identity is important for slowing the aging process. Numerous studies have shown that caloric restriction is the gold standard for promoting longevity and healthy aging in various species ranging from rodents to primates. It can be inferred that delaying of aging through the main effector such as calorie restriction is involved in cellular identity and epigenetic modification. Thus, an understanding of aging through calorie restriction may seek a more in-depth understanding. In this review, we discuss how caloric restriction promotes longevity and healthy aging through genomic stability and epigenetic alterations. We have also highlighted how the effectors of caloric restriction are involved in modulating the chromatin-based barriers.
    Keywords:  Aging; Caloric restriction; Chromosome stability; Epigenetic; Sirt1
    DOI:  https://doi.org/10.1007/s00109-024-02430-y
  13. Immun Ageing. 2024 Mar 08. 21(1): 18
    Immune aging in annual killifish.
    Gabriele Morabito, Alina Ryabova, Dario Riccardo Valenzano.
      Turquoise killifish (Nothobranchius furzeri) evolved a naturally short lifespan of about six months and exhibit aging hallmarks that affect multiple organs. These hallmarks include protein aggregation, telomere shortening, cellular senescence, and systemic inflammation. Turquoise killifish possess the full spectrum of vertebrate-specific innate and adaptive immune system. However, during their recent evolutionary history, they lost subsets of mucosal-specific antibody isoforms that are present in other teleosts. As they age, the immune system of turquoise killifish undergoes dramatic cellular and systemic changes. These changes involve increased inflammation, reduced antibody diversity, an increased prevalence of pathogenic microbes in the intestine, and extensive DNA damage in immune progenitor cell clusters. Collectively, the wide array of age-related changes occurring in turquoise killifish suggest that, despite an evolutionary separation spanning hundreds of millions of years, teleosts and mammals share common features of immune system aging. Hence, the spontaneous aging observed in the killifish immune system offers an excellent opportunity for discovering fundamental and conserved aspects associated with immune system aging across vertebrates. Additionally, the species' naturally short lifespan of only a few months, along with its experimental accessibility, offers a robust platform for testing interventions to improve age-related dysfunctions in the whole organism and potentially inform the development of immune-based therapies for human aging-related diseases.
    Keywords:  Aging; Gerontology; Immunity; Killifish; Teleosts
    DOI:  https://doi.org/10.1186/s12979-024-00418-3
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