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

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

Author information

1
Department of Anatomy and Histology, School of Medicine, Nankai University, Tianjin, 300071, China.
2
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA.
3
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA.
4
Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA.
5
Pathology Department, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, 17033, USA.
6
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21287, USA.
7
Department of Radiology and Radiologic Sciences, Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA.
8
Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA.
9
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA. justin.balko@vanderbilt.edu.
10
Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA. justin.balko@vanderbilt.edu.
11
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232-2310, USA. justin.balko@vanderbilt.edu.

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.

PMID:
29339738
PMCID:
PMC5770411
DOI:
10.1038/s41467-017-02630-w
[Indexed for MEDLINE]
Free PMC Article

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