Epigenetic silencing of Th1-type chemokines dictates effector T cell tumor trafficking and predicts patient outcome (TUM7P.1019)

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism in cancer. However, its role in cancer immunopathology and immunotherapy is poorly understood. In this study, we focused on the infiltration of effector T lymphocytes into ovarian tumor and established the histone H3 lysine 27 trimethylation (H3K27me3) and DNA hypermethylation as epigenetic silencing mechanisms regulating Th1-type chemokines CXCL9 and CXCL10 production. We found that a polycomb group (PcG) protein, enhancer of zeste 2 homolog (EZH2)-based histone H3 lysine 27 trimethylation (H3K27me3) alone or in collaboration with DNA methyltransferases (DNMTs) selectively control the tumor production of CXCL9 and CXCL10, and subsequently determine effector T cell trafficking to the tumor microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T cell tumor infiltration, slows down tumor progression, and improves therapeutic efficacy of PDL1(B7-H1) checkpoint blockade and adoptive T cell transfusion. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor infiltrating CD8 + T cells and patient outcome. Our results indicate that epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape in cancer and enhances clinical efficacy of cancer therapy.