Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism(1) However, its role in cancer immunopathology and immunotherapy is poorly understood. Using ovarian cancers as our model, we found that enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase (DNMT) 1-mediated DNA methylation repress the tumor production of Th1-type chemokines 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 PD-L1 (B7-H1) checkpoint blockade(2–4) and adoptive T cell transfusion(5) in tumor bearing mice. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape(6) in cancer and may enhance clinical efficacy of cancer therapy.