在体外扩增过程中，Tazemetostat 短暂抑制 EZH2 可维持 T 细胞干性并改善过继性 T 细胞疗法

The histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated epigenetic regulation of T cell differentiation in acute infection has been extensively investigated.

However, the role of EZH2 in T cell exhaustion remains under-explored.

Here, using in vitro exhaustion models, we demonstrated that transient inhibition of EZH2 in T cells before the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetastat, delayed their dysfunctional progression and maintained T cell stemness and polyfunctionality while having no negative impact on cell proliferation.

Tazemetestat induced T cell epigenetic reprogramming and increased the expression of the self-renewing T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells pre-treated with tazemetastat exhibited a superior response to anti-PD-1 blockade therapy after adoptive transfer. Collectively, these data unveil the potential of transient epigenetic reprogramming as a potential intervention to be combined with checkpoint blockade for immune therapy.