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Nature. 2015 Nov 12;527(7577):249-53. doi: 10.1038/nature15520. Epub 2015 Oct 26.

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

Author information

1
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
2
Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
3
Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
4
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
5
The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
6
The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
7
Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA.
8
Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
9
Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

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.

PMID:
26503055
PMCID:
PMC4779053
DOI:
10.1038/nature15520
[Indexed for MEDLINE]
Free PMC Article

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