DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer

Nat Commun. 2018 Jan 16;9(1):248. doi: 10.1038/s41467-017-02630-w.

Abstract

Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ. In murine tumor models of breast cancer, guadecitabine upregulates MHC-I in tumor cells promoting recruitment of CD8+ T cells to the microenvironment. Finally, we show that MHC-I genes are upregulated in breast cancer patients treated with hypomethylating agents. Thus, the immunomodulatory effects of hypomethylating agents likely involve upregulation of class-I antigen presentation to potentiate CD8+ T cell responses. These strategies may be useful to potentiate anti-tumor immunity and responses to checkpoint inhibition in immune-refractory breast cancers.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferase 1 / antagonists & inhibitors*
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, MHC Class I / genetics
  • Genes, MHC Class I / physiology*
  • Humans
  • Mammary Neoplasms, Experimental
  • Mice
  • Promoter Regions, Genetic
  • T-Lymphocytes, Cytotoxic / physiology*

Substances

  • Antineoplastic Agents
  • guadecitabine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • Azacitidine