EZH2 protects tumor-infiltrating lymphocytes from metabolic-stress induced cell death and exhaustion

Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TILs. T cells undergo a loss of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) during tumor infiltration. Using a multi-omics approach, we have defined a mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant metabolic exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth. Our studies suggest that manipulation of EZH2 in T cells might represent a potential strategy to protect tumor-specific T cells during metabolic stress. Overall design: Comparison of H3K27me3 and H3K36me3 ChIP-Seq on control and EZH2 inhibited T cells.