Abstract
Effective immunotherapy treats cancers by eradicating tumourigenic cells by activated tumour antigen-specific and bystander CD8+ T-cells. However, T-cells can gradually lose cytotoxicity in the tumour microenvironment, known as exhaustion. Recently, DNA methylation, histone modification, and chromatin architecture have provided novel insights into epigenetic regulations of T-cell differentiation/exhaustion, thereby controlling the translational potential of the T-cells. Thus, developing strategies to govern epigenetic switches of T-cells dynamically is critical to maintaining the effector function of antigen-specific T-cells. In this mini-review, we 1) describe the correlation between epigenetic states and T cell phenotypes; 2) discuss the enzymatic factors and intracellular/extracellular microRNA imprinting T-cell epigenomes that drive T-cell exhaustion; 3) highlight recent advances in epigenetic interventions to rescue CD8+ T-cell functions from exhaustion. Finally, we express our perspective that regulating the interplay between epigenetic changes and transcriptional programs provides translational implications of current immunotherapy for cancer treatments.
Highlights
Adaptive immunity is a physiological defensive mechanism, including fighting against cancers
Gene set enrichment analysis (GSEA) showed that CXCR5–CD8+ T cells were related to CD4+ TH1 (T helper type 1) cells and CD8+ terminal effectors, but the CXCR5+ subset was similar to CD4+ T follicular helper cells (TFH) cells and CD8 memory precursors
It is known that DNA methyltransferase (DNMT) mediates DNA methylation, which implies that DNMT participated in the process of T cell differentiation (Pace and Amigorena, 2020; Akbari et al, 2021)
Summary
Adaptive immunity is a physiological defensive mechanism, including fighting against cancers. H3K4me tag density and low H3K27me tag density This epigenetic remodeling is associated with the memory gene downregulation and effector gene upregulation in differentiated CD8+ T cells. T cell exhaustion weakens adaptive immunity that causes the failure of self-defense against tumors To address this issue, researchers have developed immune-checkpoint blockade strategies to disrupt the interaction between inhibitory ligands and receptors, thereby preventing inhibitory signals in T cells (Leach et al, 1996; Freeman et al, 2000; Iwai et al, 2005). Stimulatory/inhibitory signals initiate intracellular signal cascades through T-cell membrane receptors and alter gene expression profiles that define T cell functionality and phenotype (Gattinoni et al, 2012; Chen and Flies, 2013; Boussiotis, 2016) Those signals indirectly modulate gene methylation and histone modification (methylation of histone protein tail). In this mini-review, we discuss the correlated epigenetic profile of the respective CD8+ T cell phenotype, highlight the significant enzymatic factors and intracellular/ extracellular miRNA that regulate T cell response at the epigenetic level, and discuss the possible strategies by manipulating these factors for improved cancer treatments
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