Resumen de Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy
Dongjun Peng, Ilona Kryczek, Nisha Nagarsheth, LILI ZHAO, Shuang Wei, Weiming Wang, Yuqing Sun, Ende Zhao
Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism1. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade2,3,4 and adoptive T-cell transfusion5 in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8+ T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape6 in cancer and may enhance the clinical efficacy of cancer therapy.
