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

CD8(+) exhausted T cells (T(ex)) are heterogeneous. PD-1 inhibitors reinvigorate progenitor T(ex), which subsequently differentiate into irresponsive terminal T(ex). The ability to maintain a capacity for durable proliferation of progenitor T(ex) is important, but the mechanism remains unclear. Here, we showed CD8(+) progenitor T(ex) pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti–PD-1 treatment in vitro. Treatment with decitabine plus anti–PD-1 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 the combination of decitabine plus anti–PD-1 markedly elevated the clonal 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 the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in CD8(+) T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel CD8(+) progenitor T(ex) populations and improve responsiveness to anti–PD-1 therapy.