Application of ATAC-seq in tumor-specific T cell exhaustion

Abstract

Researches show that chronic viral infection and persistent antigen and/or inflammatory signal exposure in cancer causes the functional status of T cells to be altered, mainly by major changes in the epigenetic and metabolic environment, which then leads to T cell exhaustion. The discovery of the immune checkpoint pathway is an important milestone in understanding and reversing T cell exhaustion. Antibodies targeting these pathways have shown superior ability to reverse T cell exhaustion. However, there are still some limitations in immune checkpoint blocking therapy, such as the short-term nature of therapeutic effects and high individual heterogeneity. Assay for transposase-accessible chromatin with sequencing(ATAC-seq) is a method used to analyze the accessibility of whole-genome chromatin. It uses hyperactive Tn5 transposase to assess chromatin accessibility. Recently, a growing number of studies have reported that ATAC-seq can be used to characterize the dynamic changes of epigenetics in the process of T cell exhaustion. It has been determined that immune checkpoint blocking can only temporarily restore the function of exhausted T cells because of an irreversible change in the epigenetics of exhausted T cells. In this study, we review the latest developments, which provide a clearer molecular understanding of T cell exhaustion, reveal potential new therapeutic targets for persistent viral infection and cancer, and provide new insights for designing effective immunotherapy for treating cancer and chronic infection.

Fundamentals to therapeutics: Epigenetic modulation of CD8+ T Cell exhaustion in the tumor microenvironment

“…These techniques can be completed on bulk cells or single cells as described in this review. Created with Biorender.com and adapted from Chen et al, 2022. Frontiers in Cell and Developmental Biology frontiersin.org…”

“…For example, progenitor exhausted CD8 + T cells do not always turn into terminally exhausted subtype. Some reports suggest the existence of multiple intermediate cell subsets during this progression, if the progression occurs at all ( Yang and Wang, 2021 ; Chen et al, 2022 ). To further outline the transcriptional heterogeneity of exhausted T cells, a new exhausted CD8 + T cell subset was identified recently which expresses unique natural killer (NK) cell related genes (i.e.…”

“…Studies also have shown significant differences in regulatory region patterns between these different T cell populations with ATAC-seq, overall supporting its clear importance. Thorough reviews have been done on the application of ATAC-seq in the tumor microenvironment and we recommend their review for more information ( Sen et al, 2016 ; Chen et al, 2022 ).…”

“…One mechanism of resistance to T cell-targeting immunotherapies is loss of T cell effector activity ( Pauken et al, 2016 ; Balança et al, 2021 ), whereby dysfunctional/exhausted CD8 + T cells fail to adequately clear cancer cells. Recently, epigenetic alterations were found to reinforce the differentiation of naive T cells to the exhausted state ( Yang and Wang, 2021 ; Belk et al, 2022 ; Chen et al, 2022 ). Therefore, we and others believe that CD8 + T cells can be re-sensitized to ICB therapy by modulating the activity of specific epigenetic factors that mediate CD8 + T cell exhaustion.…”

Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities

“…Upon PD-1 ICB treatment this population is responsible for the proliferative burst, and thus, MYB could play a central role in therapeutic checkpoint blockade success (140). Other transcriptions factors found to promote exhaustion are NFAT and NR4A, while BATF attenuates exhaustion (141). The transcription factor IKZF3 is a repressor of IL-2 (142), and Hay et al ( 2022) used an in vitro model to show that exhausted T cells partially can be rescued by treatment with Lenalidomide, an IKZF3 small molecule inhibitor, either as a single treatment or in combination with ICB treatment.…”