Journal Article

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

Kryczek, Ilona, Wang, Weimin, Zhao, Ende, Dou, Yali, Zhao, Lili, Tarkowski, Rafał, Peng, Dongjun, Liu, Rebecca, Kotarski, Jan, Sun, Yuqing, Zou, Weiping, Cho, Kathleen, Hensley-Alford, Sharon, Nagarsheth, Nisha, Wei, Shuang, Munkarah, Adnan, Vatan, Linda, Szeliga, Wojciech

2015

Overview

Treating ovarian cancer in mouse models with inhibitors for the epigenetic regulators EZH2 and DNMT1 increases the expression of the inflammatory chemokines CXCL9 and CXCL10, resulting in enhanced tumour infiltration by effector T cells, and slowed tumour progression. Epigenetic reprograming and cancer immunotherapy The therapeutic response of cancer patients to immunotherapy can be variable. Weiping Zou and colleagues hypothesize that immunoprotective signature genes might be epigenetically silenced in cancer, thereby promoting cancer progression and blunting the clinical response to immunotherapy. To test this idea the authors treated ovarian cancer in mouse models with agents that inhibit the epigenetic regulators EZH2 and DNMT1. They find that inhibition of EZH2 and DNMT1 increases the expression of the inflammatory chemokines CXCL9/10, resulting in enhanced tumour infiltration by effector T cells, and slower tumour progression. 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 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 (T H 1)-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 2 , 3 , 4 and adoptive T-cell transfusion 5 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 T H 1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape 6 in cancer and may enhance the clinical efficacy of cancer therapy.

• Publisher: Nature Publishing Group UK
• Subject: 13 / 13/105 / 13/106 / 13/109 / 13/2 / 13/31 / 13/51 / 631/250 / 631/250/580 / 631/67 / Animals / B7-H1 Antigen - metabolism / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - immunology / Chemokine CXCL10 - biosynthesis / Chemokine CXCL10 - genetics / Chemokine CXCL10 - immunology / Chemokine CXCL9 - biosynthesis / Chemokine CXCL9 - genetics / Chemokine CXCL9 - immunology / Chemokines - biosynthesis / Chemokines - genetics / Chemokines - immunology / DNA (Cytosine-5-)-Methyltransferase 1 / DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA Methylation - drug effects / Enhancer of Zeste Homolog 2 Protein / Epigenesis, Genetic - drug effects / Female / Gene Silencing / Histones - chemistry / Histones - metabolism / Humanities and Social Sciences / Humans / Immunotherapy - methods / letter / Lymphocytes, Tumor-Infiltrating - immunology / Lysine - metabolism / Mice / multidisciplinary / Ovarian Neoplasms - enzymology / Ovarian Neoplasms - immunology / Ovarian Neoplasms - pathology / Ovarian Neoplasms - therapy / Polycomb Repressive Complex 2 - antagonists & inhibitors / Polycomb Repressive Complex 2 - metabolism / Prognosis / Science / Th1 Cells - immunology / Th1 Cells - metabolism / Tumor Cells, Cultured / Tumor Escape - immunology / Xenograft Model Antitumor Assays