Decitabine priming increases anti–PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models

Abstract

CD8 + exhausted T-cells (T ex ) are heterogeneous. PD-1 inhibitors reinvigorate progenitor T ex , which subsequently differentiate into irresponsive terminal T ex .Maintaining durable proliferative capacity of progenitor T ex is important but remains unclear. Here, we showed that low-dose DNA demethylating agent decitabine-pretreated CD8 + progenitor T ex had enhanced proliferation and effector function against tumors after anti-PD-1 treatment in vitro. Decitabine-plus-anti-PD-1 treatment promoted the activation and expansion of tumor-infiltrated CD8 + progenitor T ex and efficiently suppressed tumor growth in multiple tumor models.Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that decitabine-plus-anti-PD-1 combination markedly elevated the clonally expansion and cytolytic activity of progenitor T ex compared with anti-PD-1 monotherapy and restrained CD8 + T-cell terminal differentiation. Strikingly, decitabine-plus-anti-PD-1 sustained the expression and activity of AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation and activating JNK/AP-1 signaling in CD8 + T-cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agent remodels CD8 + progenitor T ex and improves responsiveness to anti-PD-1 therapy.

Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment

“…De novo DNA methylation, especially DNA methyltransferases 3A (DNMT3A)-dependent DNA methylation events, happened in some specific genes during the differentiation of TEXs. The Ccr7 and Tcf7 loci remained demethylated in Tpex (19,42). However, in terminally exhausted T cells, genes involved in proliferation, tissue homing, metabolic activity and effector function (Tcf7, Ccr7, Myc and ifng) were acquired severe de novo DNA methylation, contributing to their low expression and terminal exhaustion differentiation (19,42).…”

“…The Ccr7 and Tcf7 loci remained demethylated in Tpex (19,42). However, in terminally exhausted T cells, genes involved in proliferation, tissue homing, metabolic activity and effector function (Tcf7, Ccr7, Myc and ifng) were acquired severe de novo DNA methylation, contributing to their low expression and terminal exhaustion differentiation (19,42).…”

“…The De novo DNA methylation, especially DNA methyltransferases 3A (DNMT3A)-dependent DNA methylation events in some specific genes promoted the progression of terminal exhaustion (19,42). Application of DNA demethylating agents Decitabine (DAC) or DNMT3A knockout CAR-T cells effectively inhibited the de novo DNA methylation of exhaustion-related genes (13,42).…”

“…In addition, metabolism-based therapy greatly improves metabolic defeats in TEXs. Combination therapy such as "ICB + metabolism-based therapy" and "ICB + cytokine therapy" showed superior efficacy and better tumor control than anti-PD1 monotherapy (5,(18)(19)(20)(21). In this review, we focus on the main strategies to reinvigorate exhausted CD8 + T cells in TME.…”

Single‐cell RNA sequencing gene signatures for classifying and scoring exhausted CD8+ T cells in B‐cell acute lymphoblastic leukaemia

“…7,8 The progression of T cell exhaustion occurs gradually, leading to the emergence of distinct CD8_Ex subgroups including progenitor CD8_Ex cells and terminal CD8_Ex cells. 9 Progenitor CD8_Ex cells demonstrate higher reprogramability, maintain their proliferative capacity and expand following PD-1/PD-L1 blockade. 10 In contrast, terminal CD8_Ex cells are non-reprogrammable and unable to proliferate after PD-1/PD-L1 blockade.…”