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EZH2 protects tumor-infiltrating lymphocytes from metabolic-stress induced cell death and exhaustion [RNA-seq]

ABSTRACT: Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TILs. T cells undergo a loss of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) during tumor infiltration. Using a multi-omics approach, we have defined a mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant metabolic exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth. Our studies suggest that manipulation of EZH2 in T cells might represent a potential strategy to protect tumor-specific T cells during metabolic stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE143262 | GEO | 2020/12/31

REPOSITORIES: GEO

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EZH2 protects tumor-infiltrating lymphocytes from metabolic-stress induced cell death and exhaustion

Project description:Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TILs. T cells undergo a loss of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) during tumor infiltration. Using a multi-omics approach, we have defined a mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant metabolic exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth. Our studies suggest that manipulation of EZH2 in T cells might represent a potential strategy to protect tumor-specific T cells during metabolic stress.

2020-12-31 | GSE142454 | GEO

PD-L1 overexpression, SWI/SNF complex Deregulation and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells

Project description:The growing tumor avoids recognition and destruction by immune system. During continuous stimulation of tumor infiltrating lymphocytes (TILs) by tumor, TILs become functionally exhausted. Thus, they become unable to kill tumor cells and to produce some cytokines, and lose their ability to proliferate. It collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level on cell surface, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cells number. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell line overexpressing PD-L1 that suggested the existence of general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on PD-L1 promoter region indicated that the strong BRM recruitment in control CD4+ T cells is replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that such epi-drugs as EZH2 inhibitors may be used as immunomodulators in cancer treatment.

2022-02-17 | PXD026447 | Pride

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy

Project description:Identifying signals that govern the differentiation of tumor-infiltrating CD8 + T cells (CD8 + TILs) towards exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues enhancing terminal CD8 + T cell exhaustion in tumors. We found enrichment of IFNIs-stimulated genes (ISGs) within exhausted CD8 + T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8 + TILs devoid of IFN-Is signaling developed less exhaustion features, provided better tumor control and showed greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-Is stimulation perturbed lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promoted lipid peroxidation, which potentiated metabolic and functional exhaustion of Tex cells. Thus, cell intrinsic IFN-Is signaling regulates the extent of CD8+ TIL exhaustion, and has important implications for immunotherapy.

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Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [ATAC-Seq]

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Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [RNA-Seq]

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Transcriptome differences in HCC infiltrated CD8+ T cells in effector and exhaustion state

Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.

2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress

Disturbed mitochondrial dynamics in CD8+ TIL reinforce epigenetic programming linked with T cell exhaustion

Project description:The metabolic challenges present in tumors attenuate the metabolic fitness and anti-tumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulating depolarized mitochondria as a result of declined mitophagy activity display functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, declined mitochondrial fitness in TILs is induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signal. Forcing the accumulation of depolarized mitochondria with pharmacological interventions induces epigenetic reprogramming for terminal exhaustion, indicating that mitochondrial deregulation is indeed a cause – rather than a consequence – of T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal new insights on how mitochondrial dynamics and quality orchestrate T cell anti-tumor responses and commitment to the exhaustion program.

2020-09-01 | GSE144583 | GEO

Disturbed mitochondrial dynamics in CD8+ TIL reinforce epigenetic programming linked with T cell exhaustion

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Disturbed mitochondrial dynamics in CD8+ TIL reinforce epigenetic programming linked with T cell exhaustion [RNA-Seq]

2020-09-01 | GSE156506 | GEO

Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells (OT-I vs P14 RNA-seq)

Project description:T cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8+ tumor-infiltrating lymphocytes (TIL) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, non-exhausted, TIL and in acutely restimulated CD8+ T cells, we define a pattern of chromatin accessibility specific for T cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti-PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TIL, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T cell exhaustion in cancer and other inflammatory settings.

2017-02-28 | GSE93006 | GEO

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