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

Abstract

In the setting of chronic antigen exposure in the tumor microenvironment (TME), cytotoxic CD8+ T cells (CTLs) lose their immune surveillance capabilities and ability to clear tumor cells as a result of their differentiation into terminally exhausted CD8+ T cells. Immune checkpoint blockade (ICB) therapies reinvigorate exhausted CD8+ T cells by targeting specific inhibitory receptors, thus promoting their cytolytic activity towards tumor cells. Despite exciting results with ICB therapies, many patients with solid tumors still fail to respond to such therapies and patients who initially respond can develop resistance. Recently, through new sequencing technologies such as the assay for transposase-accessible chromatin with sequencing (ATAC-seq), epigenetics has been appreciated as a contributing factor that enforces T cell differentiation toward exhaustion in the TME. Importantly, specific epigenetic alterations and epigenetic factors have been found to control CD8+ T cell exhaustion phenotypes. In this review, we will explain the background of T cell differentiation and various exhaustion states and discuss how epigenetics play an important role in these processes. Then we will outline specific epigenetic changes and certain epigenetic and transcription factors that are known to contribute to CD8+ T cell exhaustion. We will also discuss the most recent methodologies that are used to study and discover such epigenetic modulations. Finally, we will explain how epigenetic reprogramming is a promising approach that might facilitate the development of novel exhausted T cell-targeting immunotherapies.

Degradation of IKAROS prevents epigenetic progression of T cell exhaustion in a novel antigen-specific assay

“…Despite the necessity of epigenetic remodeling in the progression of exhaustion, targeting epigenetic factors to restore exhausted T cell function has been challenging. Employing pleotropic agents such as Dnmt1i 62 , HDACi 63 and even more focused inhibitors targeting readers (BETi ) 64,65 and HMT (EZH2i) 14,15,16 have had limited clinical success in treating tumors. Identification of the TF families Tox and NR4A as exhaustion regulators [66][67][68][69] has been similarly challenging to translate to therapies due to difficulty in druggability.…”

“…Epigenetically reprogramming exhausted T cells to a responsive state could enable broader and perhaps deeper responses to cancer immunotherapies across indications. Towards this end, epigenomic modifications such as pharmacologic inhibition of DNA demethylation 5 , histone deacetylases 10,11 , SWI/SNF 12,13 , and EZH2 14,15,16 have been reported to rescue aspects of T cell exhaustion. However, current understanding of T cell exhaustion comes mostly from chronic viral infection and syngeneic tumor studies in mice.…”

Myeloid-derived suppressor cells-induced exhaustion of CD8 + T-cell participates in rejection after liver transplantation

“…After prolonged exposure to antigens, immune responses of T cells gradually wane and may eventually result in a functional impairment [ 42 ]. These impaired T cells fail to differentiate into memory T cells and subsequently evolve into exhausted T cells [ 43 ]. We found that a large number of PD-1+ exhausted T cells were present in PBMC from LT patients, which indicates that some of these CD8 + T cells have become “exhausted”.…”

The role of the CD8+ T cell compartment in ageing and neurodegenerative disorders

“…The development of senolytic small-molecules that can specifically eliminate senescent cells, may represent a promising strategy for treating multiple CD8+ T cell senescent-mediated disorders and age-related conditions in humans (197). Also, the epigenetic modulation of senescent and exhausted CD8+ T cells involving small molecules and biologics to target the molecular pathways involved in developing and maintaining these cell types, can modify the senescence and exhaustion, potentially reversing these deleterious phenotypes (198)(199)(200). For example, it has been recently observed that EZH2expressing T cells are precursors to KLRG1+ effector lymphocytes, while EZH2 LOW -expressing T cells predominantly produce noncytotoxic CD103+ CD69+ TRM CD8+ T cells (201).…”