Abstract LB339: Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy

Abstract The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T cell differentiation, proliferation and function. Previous studies demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and expansion upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we demonstrate that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delays their dysfunctional progression and preserves T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetostat induces T-cell epigenetic reprogramming and increases the expression of the self-renewal T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induce poor tumor control, whereas T cells pretreated with tazemetostat exhibited superior anti-tumor immunity, especially when used in combination with anti-PD-1 blockade after adoptive transfer. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T cell immunotherapy. Citation Format: Yingqin Hou, Peng Wu. Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB339.