Epigenetic Silencing of TH1-type Chemokines Shapes Tumour Immunity and Immunotherapy

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Humans
  • Immunotherapy* / methods
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lysine / metabolism
  • Mice
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Polycomb Repressive Complex 2 / antagonists & inhibitors
  • Polycomb Repressive Complex 2 / metabolism
  • Prognosis
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Tumor Cells, Cultured
  • Tumor Escape / immunology
  • Xenograft Model Antitumor Assays

Substances

  • B7-H1 Antigen
  • CXCL10 protein, human
  • CXCL9 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL9
  • Chemokines
  • Histones
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Lysine