bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–03–09
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.
  2. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate.
  3. Metabolic engineering to facilitate anti-tumor immunity.
  4. Metabolic alterations in HSCs during aging and leukemogenesis.
  5. Ferroptosis of T cell in inflammation and tumour immunity.
  6. T cell exhaustion: early or late in tumour progression?
  7. Enhancing T cell therapy.
  8. Collaboration between interleukin-7 and -15 enables adaptation of tissue-resident and circulating memory CD8+ T cells to cytokine deficiency.
  9. CD36 Promotes Iron Accumulation and Dysfunction in CD8+ T Cells via the p38-CEBPB-TfR1 Axis in Early-stage Hepatocellular Carcinoma.
  1. JCI Insight. 2025 Mar 04. pii: e174600. [Epub ahead of print]
    Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.
    Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu.
      This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T cells (Tex) in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome alterations in Tex, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and anti-tumor capacity of Tex, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex, accompanied by a significant reduction in the metabolic intermediate L-2-HG level. Moreover, altered epigenetic characteristics was observed in Tex, including a substantial increase in H3K27me3 abundance. Culturing Tex with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In the mouse melanoma tumor model, L-2-HG-treated CD8+T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed L-2-HG acted as an immune metabolite through epigenetic modifications of Tex.
    Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells
    DOI:  https://doi.org/10.1172/jci.insight.174600
  2. Sci Immunol. 2025 Mar 07. 10(105): eado3032
    Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate.
    Yinghui J Huang, Shin Foong Ngiow, Amy E Baxter, Sasikanth Manne, Simone L Park, Jennifer E Wu, Omar Khan, Josephine R Giles, E John Wherry.
      Although checkpoint blockade temporarily improves exhausted CD8 T (Tex) cell function, the underlying Tex epigenetic landscape remains largely unchanged, preventing durable Tex "reinvigoration" in cancer and chronic infections. The transcription factor TOX initiates Tex epigenetic programming, yet it remains unclear whether TOX continually preserves Tex biology after Tex establishment. Here, we demonstrated that induced TOX ablation in committed Tex cells resulted in apoptotic-driven loss of Tex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed Tex cells. Moreover, TOX removal endows established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established Tex cells acts as a durable epigenetic barrier reinforcing the Tex developmental fate. TOX manipulation even after Tex establishment could therefore provide therapeutic opportunities to rewire Tex cells in chronic infections or cancer.
    DOI:  https://doi.org/10.1126/sciimmunol.ado3032
  3. Cancer Cell. 2025 Feb 21. pii: S1535-6108(25)00056-X. [Epub ahead of print]
    Metabolic engineering to facilitate anti-tumor immunity.
    Tanya Schild, Patrick Wallisch, Yixuan Zhao, Ya-Ting Wang, Lyric Haughton, Rachel Chirayil, Kaitlyn Pierpont, Kevin Chen, Sara Nunes-Violante, Justin Cross, Elisa de Stanchina, Craig B Thompson, David A Scheinberg, Justin S A Perry, Kayvan R Keshari.
      Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8+ T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions in vitro. GLUT5-expressing T cells show high fructolytic activity in vitro and higher anti-tumor efficacy in murine syngeneic and human xenograft models in vivo, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME.
    Keywords:  CAR-T; fructose; macrophages; metabolic engineering; slc2a5; t cell
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.004
  4. Physiology (Bethesda). 2025 Feb 28.
    Metabolic alterations in HSCs during aging and leukemogenesis.
    Yi-Hsuan Chiang, Stephan Emmrich, Nicola Vannini.
      Aging is a multifaceted process associated with a functional decline in cellular function over time, affecting all lifeforms. During the aging process, metabolism, a fundamental hallmark of life (1), is profoundly altered. In the context of hematopoiesis, the proper function of hematopoietic stem cells - at the apex of the blood system - is tightly linked to their energy metabolism, which in turn shapes hematopoietic output. Here, we review the latest developments in our understanding of the metabolic states and changes in aged hematopoietic stem cells, molecular players and pathways involved in aged hematopoietic stem cell metabolism, the consequences of perturbed metabolism on clonal hematopoiesis and leukemogenesis, and pharmacologic/ genetic strategies to reverse or rejuvenate altered metabolic phenotypes.
    Keywords:  aging; clonal hematopoiesis; hematopoietic stem cell; leukemogenesis; metabolism
    DOI:  https://doi.org/10.1152/physiol.00054.2024
  5. Clin Transl Med. 2025 Mar;15(3): e70253
    Ferroptosis of T cell in inflammation and tumour immunity.
    Xueli Xia, Haisheng Wu, Yuxuan Chen, Huiyong Peng, Shengjun Wang.
      Ferroptosis is an innovative concept defined as a distinct programmed cell death mode regulated by iron-dependent lipid peroxidation accumulation. This process is governed by numerous energy metabolites such as fatty acids, amino acids and glucose, as well as iron homeostasis. In recent years, increasing studies have been devoted to the crucial effects of ferroptosis in immune cells during the pathogenesis of diseases such as infections, tumours and autoimmune disorders. This review summarises the latest advancements in T-cell ferroptosis, addresses the key components and mechanism of ferroptosis in T cells during inflammatory conditions and tumour progression, and highlights the potential target for treating related diseases. KEY POINTS: Ferroptosis-related mechanisms significantly affect the biology of CD4+ T-cell subsets and are further involved in inflammatory diseases. Crosstalk between CD8+ T cells and tumour cells induces ferroptosis in the tumour microenvironment. Glutathione peroxidase 4 loss promotes regulatory T-cell ferroptosis to enhance anti-tumour immunity.
    Keywords:  CD4+ T cell; CD8+ T cell; ferroptosis; inflammation; tumour
    DOI:  https://doi.org/10.1002/ctm2.70253
  6. Nat Rev Immunol. 2025 Mar 04.
    T cell exhaustion: early or late in tumour progression?
    Lorenzo Galluzzi.
      
    DOI:  https://doi.org/10.1038/s41577-025-01158-1
  7. Nat Immunol. 2025 Mar;26(3): 330
    Enhancing T cell therapy.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-025-02109-7
  8. Immunity. 2025 Feb 21. pii: S1074-7613(25)00076-7. [Epub ahead of print]
    Collaboration between interleukin-7 and -15 enables adaptation of tissue-resident and circulating memory CD8+ T cells to cytokine deficiency.
    Nicholas N Jarjour, Talia S Dalzell, Nicholas J Maurice, Kelsey M Wanhainen, Changwei Peng, Stephen D O'Flanagan, Taylor A DePauw, Katharine E Block, William J Valente, K Maude Ashby, David Masopust, Stephen C Jameson.
      Interleukin-7 (IL-7) is considered a critical regulator of memory CD8+ T cell homeostasis. However, this is primarily based on circulating memory populations, and the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Here, we addressed the role for IL-7Rα in circulating and resident memory CD8+ T cells (Trm) after their establishment. We found that inducible Il7ra deletion had only a modest effect on persistence of circulating memory and Trm subsets, causing reduced basal proliferation. Loss of IL-15 signaling imposed heightened IL-7Rα dependence on memory CD8+ T cells, including Trm cells described as IL-15 independent. In the absence of IL-15 signaling, IL-7Rα was elevated, and loss of IL-7Rα signaling reduced IL-15-elicited proliferation, suggesting crosstalk between these pathways in memory CD8+ T cells. Thus, across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8+ T cells, conferring resilience to altered availability of either cytokine.
    Keywords:  CD8(+) T cells; adaptive immunity; immune memory; interleukin-15; interleukin-7; interleukin-7 receptor α; memory homeostasis; proliferation
    DOI:  https://doi.org/10.1016/j.immuni.2025.02.009
  9. Clin Mol Hepatol. 2025 Mar 04.
    CD36 Promotes Iron Accumulation and Dysfunction in CD8+ T Cells via the p38-CEBPB-TfR1 Axis in Early-stage Hepatocellular Carcinoma.
    Yifei Qin, Fei Huo, Zhuan Feng, Jialu Hou, Yaxin Ding, Quancheng Wang, Yu Gui, Ziwei Yang, Jiali Yang, Gang Zhou, Ling Li, Jianli Jiang, Lingmin Kong, Shijie Wang, Gang Nan, Dingqiao Xu, Xiaohang Xie, Lijuan Wang, Qian He, Ruibin Yang, Peng Lin, Huijie Bian, Zhi-Nan Chen, Jiao Wu.
       Background: The identification of factors that lead to CD8⁺ T cell dysfunction within the tumor microenvironment (TME) holds great promise for the development of innovative immunotherapies. However, the precise mechanisms underlying the exhausted phenotype of CD8⁺ T cells infiltrating early-stage hepatocellular carcinoma (HCC) tumors remains unclear.
    Methods: Single-cell RNA sequencing was performed using a murine HCC model. Flow cytometry and additional experimental approaches were employed to investigate the underlying mechanisms of CD8⁺ T cell exhaustion.
    Results: CD8+ T cells infiltrating early-stage HCC tumors exhibited a functionally exhausted phenotype, which escalated with HCC progression. At early stages of murine and human HCC tumors, the TME was characterized by significant iron accumulation. Moreover, tumor-infiltrating CD8+ T cells in early-stage murine HCC tumors exhibited higher levels of intracellular ferrous iron compared to splenic CD8+ T cells. This excessive iron led to increased lipid peroxide levels and impaired the effector function of CD8+ T cells. Mechanistically, CD36 upregulated the major iron uptake protein transferrin receptor 1 (TfR1) by mediating the activation of oxidized low-density lipoprotein (oxLDL)-p38-CEBPB axis. Depletion of CD36 in CD8+ T cells inhibited the upregulation of TfR1 expression and the increase of intracellular ferrous iron levels triggered by iron-enriched conditions. Furthermore, constitutively activated nuclear factor erythroid 2-related factor 2 (NRF2) effectively suppressed iron accumulation and lipid peroxidation, thereby preserving the effector functions of intratumoral CD8+ T cells and ultimately inhibiting tumor growth.
    Conclusions: Our findings reveal a previously unidentified mechanism mediated by CD36 that regulating the progressive dysfunction of CD8+ T cells in early HCC TME and provide a potential novel therapeutic approach to restore T cells function.
    Keywords:  CD36; CD8+ T dysfunction; Hepatocellular carcinoma; Iron accumulation; Lipid peroxidation
    DOI:  https://doi.org/10.3350/cmh.2024.0948
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