Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

D Peng, I Kryczek, N Nagarsheth, L Zhao, S Wei… - Nature, 2015 - nature.com
D Peng, I Kryczek, N Nagarsheth, L Zhao, S Wei, W Wang, Y Sun, E Zhao, L Vatan…
Nature, 2015nature.com
Epigenetic silencing including histone modifications and DNA methylation is an important
tumorigenic mechanism. 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 …
Abstract
Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. 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 blockade,, and adoptive T-cell transfusion 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 landscape in cancer and may enhance the clinical efficacy of cancer therapy.
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