bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024‒10‒20
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Regulation of CD8+ T cells by lipid metabolism in cancer progression.
  2. Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.
  3. Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.
  4. Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
  5. Transcriptional rewiring in CD8+ T cells: implications for CAR-T cell therapy against solid tumours.
  6. CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
  7. PD-1 and LAG-3: synergistic fostering of T cell exhaustion.
  8. Acetylcysteine synergizes PD-1 blockers against colorectal cancer progression by promoting TCF1+PD1+CD8+ T cell differentiation.
  9. Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells.
  10. BRD4 inhibitor reduces exhaustion and blocks terminal differentiation in CAR-T cells by modulating BATF and EGR1.
  11. Stimulator of interferon gene facilitates recruitment of effector CD8 T cells that drive neurofibromatosis type 1 nerve tumor initiation and maintenance.
  12. Waste management and cell death in T cells.
  1. Cell Mol Immunol. 2024 Oct 14.
    Regulation of CD8+ T cells by lipid metabolism in cancer progression.
    Yong Tang, Ziqing Chen, Qianying Zuo, Yibin Kang.
      Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.
    Keywords:  CD8+T cells; Immunotherapy; Lipid metabolism; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1038/s41423-024-01224-z
  2. Nat Immunol. 2024 Oct 16.
    Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.
    Renqiang Sun, Hongbo Chi.
      
    DOI:  https://doi.org/10.1038/s41590-024-01991-x
  3. bioRxiv. 2024 Oct 11. pii: 2024.10.07.617124. [Epub ahead of print]
    Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.
    Katelynn R Kazane, Lara Labarta-Bajo, Dina R Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C Weldon, Pieter C Dorrestein, Elina I Zúñiga.
      Chronic infections drive a CD8 T cell program termed T cell exhaustion, characterized by reduced effector functions. While cell-intrinsic mechanisms underlying CD8 T cell exhaustion have been extensively studied, the impact of the metabolic environment in which exhausted CD8 T cells (Tex) operate remains less clear. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model we investigated systemic metabolite changes early and late following acute versus chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the acute phase of the sustained infection. This included nutrient changes that were independent of viral loads and partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acid (FA) and acylcarnitines during the early phase after chronic infection. During this time, virus-specific CD8 T cells from chronically infected mice exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly stem-like Tex (Tex STEM ), a subset that generates effector-like Tex INT which directly limit viral replication. Notably, only Tex STEM increased oxidative metabolism and ATP production upon FA exposure. Consistently, short-term reintroduction of FA during late chronic infection exclusively improved Tex STEM mitochondrial fitness, percentages and numbers. This treatment, however, also reduced Tex INT , resulting in compromised viral control. Our study offers a valuable resource for investigating the role of specific metabolites in regulating immune responses during acute and chronic viral infections and highlights the potential of long-chain FA to influence Tex STEM and viral control during a protracted infection.Significance: This study examines systemic metabolite changes during acute and chronic viral infections. Notably, we identified an early, transient nutrient shift in chronic infection, marked by an increase in medium- and long-chain fatty acid related species. Concomitantly, a virus-specific stem-like T cell population, essential for maintaining other T cells, displayed high lipid avidity and was capable of metabolizing exogenous fatty acids. Administering fatty acids late in chronic infection, when endogenous lipid levels had normalized, expanded this stem-like T cell population and enhanced their mitochondrial fitness. These findings highlight the potential role of fatty acids in regulating stem-like T cells in chronic settings and offer a valuable resource for studying other metabolic signatures in both acute and persistent infections.
    DOI:  https://doi.org/10.1101/2024.10.07.617124
  4. Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00103-5. [Epub ahead of print]389 67-103
    Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
    Sanjay Pandey, Vandana Anang, Michelle M Schumacher.
      Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).
    Keywords:  AMPK; CAR-T; Fatty acid oxidation; Glycolysis; HIF1α; MTOR; Metabolism; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial metabolism; OXPHOS; T cell exhaustion; T cell metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.07.003
  5. Front Immunol. 2024 ;15 1412731
    Transcriptional rewiring in CD8+ T cells: implications for CAR-T cell therapy against solid tumours.
    Shamini Srinivasan, Jesse Armitage, Jonas Nilsson, Jason Waithman.
      T cells engineered to express chimeric-antigen receptors (CAR-T cells) can effectively control relapsed and refractory haematological malignancies in the clinic. However, the successes of CAR-T cell therapy have not been recapitulated in solid tumours due to a range of barriers such as immunosuppression, poor infiltration, and tumour heterogeneity. Numerous strategies are being developed to overcome these barriers, which include improving culture conditions and manufacturing protocols, implementing novel CAR designs, and novel approaches to engineering the T cell phenotype. In this review, we describe the various emerging strategies to improve CAR T cell therapy for solid tumours. We specifically focus on new strategies to modulate cell function and fate that have precipitated from the growing knowledge of transcriptional circuits driving T cell differentiation, with the ultimate goal of driving more productive anti-tumour T cell immunity. Evidence shows that enrichment of particular phenotypic subsets of T cells in the initial cell product correlates to improved therapeutic responses and clinical outcomes. Furthermore, T cell exhaustion and poor persistence are major factors limiting therapeutic efficacy. The latest preclinical work shows that targeting specific master regulators and transcription factors can overcome these key barriers, resulting in superior T cell therapeutic products. This can be achieved by targeting key transcriptional circuits promoting memory-like phenotypes or sustaining key effector functions within the hostile tumour microenvironment. Additional discussion points include emerging considerations for the field such as (i) targeting permutations of transcription factors, (ii) transient expression systems, (iii) tissue specificity, and (iv) expanding this strategy beyond CAR-T cell therapy and cancer.
    Keywords:  CAR-T cell; CD8+ T cell; adoptive cell therapy (ACT); cancer; immunotherapy; solid tumour; transcription factor
    DOI:  https://doi.org/10.3389/fimmu.2024.1412731
  6. Immunity. 2024 Oct 09. pii: S1074-7613(24)00457-6. [Epub ahead of print]
    CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
    Jana L Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil Kc, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P Connelly, Shondra M Pruett-Miller, Miguel Reina-Campos, Ananda W Goldrath, Yasmine Belkaid, Hongbo Chi.
      Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes-Flcn, Ragulator, and Rag GTPases-inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.
    Keywords:  CD8 T cell; adaptive immunity; dietary intervention; immunometabolism; lysosome; mitochondria; tissue-resident memory
    DOI:  https://doi.org/10.1016/j.immuni.2024.09.013
  7. Signal Transduct Target Ther. 2024 Oct 18. 9(1): 291
    PD-1 and LAG-3: synergistic fostering of T cell exhaustion.
    Maike Hofmann, Robert Thimme, Wolfgang W Schamel.
      
    DOI:  https://doi.org/10.1038/s41392-024-02000-1
  8. Cell Commun Signal. 2024 Oct 17. 22(1): 503
    Acetylcysteine synergizes PD-1 blockers against colorectal cancer progression by promoting TCF1+PD1+CD8+ T cell differentiation.
    Wenchang Zhou, Mengdi Qu, Ying Yue, Ziwen Zhong, Ke Nan, Xingfeng Sun, Qichao Wu, Jie Zhang, Wankun Chen, Changhong Miao.
      BACKGROUND: Programmed cell death protein 1 (PD-1) blockade is essential in treating progressive colorectal cancer (CRC). However, some patients with CRC do not respond well to immunotherapy, possibly due to the exhaustion of CD8+ T cells in the tumor microenvironment. N-Acetylcysteine (NAC) can reduce CD8+ T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8+ T cell differentiation remain unclear. Hence, in this study, we aimed to investigate whether NAC has a synergistic effect with PD-1 blockers against CRC progression.METHODS: We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8 + T cell differentiation and its potential mechanism were explored using cell flow assay and other studies in vitro and ex vivo.
    RESULTS: We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model mediated by CD8+ T cells. We further found that NAC can induce TCF1+PD1+CD8+ T cell differentiation and reduce the formation of exhausted T cells in vitro and in vivo. Moreover, NAC enhanced the expression of Glut4 in CD8+ T cells, promoting the differentiation of TCF1+PD1+CD8+ T cells.
    CONCLUSIONS: Our study provides a novel idea for immunotherapy for clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8+ T cell differentiation.
    Keywords:  Acetylcysteine; CD8+ T lymphocytes; Colorectal cancer; Glucose transporter 4; PD-1 blockade
    DOI:  https://doi.org/10.1186/s12964-024-01848-8
  9. bioRxiv. 2024 Oct 11. pii: 2024.10.07.617092. [Epub ahead of print]
    Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells.
    Ching-Huang Ho, Maxwell A Dippel, Meghan S McQuade, Arpit Mishra, Stephan Pribitzer, LeAnn P Nguyen, Samantha Hardy, Harshpreet Chandok, Florence Chardon, Troy A McDiarmid, Hannah A DeBerg, Jane H Buckner, Jay Shendure, Carl G de Boer, Michael H Guo, Ryan Tewhey, John P Ray.
      Genetic variants associated with autoimmune diseases are highly enriched within putative cis -regulatory regions of CD4 + T cells, suggesting that they alter disease risk via changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. We tested >18,000 autoimmune disease-associated variants for allele-specific expression using massively parallel reporter assays in primary human CD4 + T cells. The 545 expression-modulating variants (emVars) identified greatly enrich for likely causal variants. We provide evidence that many emVars are mediated by common upstream regulatory conduits, and that putative target genes of primary T cell emVars are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis -regulatory elements modulate both known and novel target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.
    DOI:  https://doi.org/10.1101/2024.10.07.617092
  10. Biomark Res. 2024 Oct 15. 12(1): 124
    BRD4 inhibitor reduces exhaustion and blocks terminal differentiation in CAR-T cells by modulating BATF and EGR1.
    Songnan Sui, Mengjun Zhong, Shuxin Zhong, Xueting Peng, Lipeng Mao, Cunte Chen, Chengwu Zeng, Oscar Junhong Luo, Yangqiu Li.
      BACKGROUND: Exhaustion is a key factor that influences the efficacy of chimeric antigen receptor T (CAR-T) cells. Our previous study demonstrated that a bromodomain protein 4 (BRD4) inhibitor can revise the phenotype and function of exhausted T cells from leukemia patients. This study aims to elucidate the mechanism by which a BRD4 inhibitor reduces CAR-T cell exhaustion using single-cell RNA sequencing (scRNA-Seq).METHODS: Exhausted CD123-specific CAR-T cells were prepared by co-culture with CD123 antigen-positive MV411 cells. After elimination of MV411 cells and upregulation of inhibitory receptors on the surface, exhausted CAR-T cells were treated with a BRD4 inhibitor (JQ1) for 72 h. The CAR-T cells were subsequently isolated, and scRNA-Seq was conducted to characterize phenotypic and functional changes in JQ1-treated cells.
    RESULTS: Both the proportion of exhausted CD8+ CAR-T cells and the exhausted score of CAR-T cells decreased in JQ1-treated compared with control-treated cells. Moreover, JQ1 treatment led to a higher proportion of naïve, memory, and progenitor exhausted CD8+ CAR-T cells as opposed to terminal exhausted CD8+ CAR-T cells accompanied by enhanced proliferation, differentiation, and activation capacities. Additionally, with JQ1 treatment, BATF activity and expression in naïve, memory, and progenitor exhausted CD8+ CAR-T cells decreased, whereas EGR1 activity and expression increased. Interestingly, AML patients with higher EGR1 and EGR1 target gene ssGSEA scores, coupled with lower BATF and BATF target gene ssGSEA scores, had the best prognosis.
    CONCLUSIONS: Our study reveals that a BRD4 inhibitor can reduce CAR-T cell exhaustion and block exhausted T cell terminal differentiation by downregulating BATF activity and expression together with upregulating EGR1 activity and expression, presenting an approach for improving the effectiveness of CAR-T cell therapy.
    Keywords:  BRD4 inhibitor; Chimeric antigen receptor T cell exhaustion; Single-cell RNA sequencing; Transcriptional factors
    DOI:  https://doi.org/10.1186/s40364-024-00667-w
  11. Sci Adv. 2024 Oct 18. 10(42): eado6342
    Stimulator of interferon gene facilitates recruitment of effector CD8 T cells that drive neurofibromatosis type 1 nerve tumor initiation and maintenance.
    Jay Pundavela, Samantha Anne Dinglasan, Melissa Touvron, Sarah A Hummel, Liang Hu, Tilat A Rizvi, Kwangmin Choi, David A Hildeman, Nancy Ratner.
      Plexiform neurofibromas (PNFs) are benign nerve tumors driven by loss of the NF1 tumor suppressor in Schwann cells. PNFs are rich in immune cells, but whether immune cells are necessary for tumorigenesis is unknown. We show that inhibition of stimulator of interferon gene (STING) reduces plasma CXCL10, tumor T cell and dendritic cell (DC) recruitment, and tumor formation. Further, mice lacking XCR-1+ DCs showed reduced tumor-infiltrating T cells and PNF tumors. Antigen-presenting cells from tumor-bearing mice promoted CD8+ T cell proliferation in vitro, and PNF T cells expressed high levels of CCL5, implicating T cell activation. Notably, tumors and nerve-associated macrophages were absent in Rag1-/-; Nf1f/f; DhhCre mice and adoptive transfer of CD8+ T cells from tumor-bearing mice restored PNF initiation. In this setting, PNF shrunk upon subsequent T cell removal. Thus, STING pathway activation contributes to CD8+ T cell-dependent inflammatory responses required for PNF initiation and maintenance.
    DOI:  https://doi.org/10.1126/sciadv.ado6342
  12. Nat Cell Biol. 2024 Oct 16.
    Waste management and cell death in T cells.
    Douglas R Green.
      
    DOI:  https://doi.org/10.1038/s41556-024-01538-0
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