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

Na Luo, Mellissa J. Nixon, Paula I. Gonzalez-Ericsson, Violeta Sanchez, Susan R. Opalenik, Huili Li, Cynthia Zahnow, Michael L. Nickels, Fei Liu, Mohammed N. Tantawy, Melinda E. Sanders, H. Charles Manning, Justin M. Balko

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number248
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Histocompatibility
T-cells
lymphocytes
Methyltransferases
Cytotoxic T-Lymphocytes
breast
Tumors
Up-Regulation
deoxyribonucleic acid
cancer
Breast Neoplasms
tumors
DNA
MHC Class I Genes
Neoplasms
Antigen Presentation
immunity
antigens
T-Lymphocytes
genes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Luo, N., Nixon, M. J., Gonzalez-Ericsson, P. I., Sanchez, V., Opalenik, S. R., Li, H., ... Balko, J. M. (2018). DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nature Communications, 9(1), [248]. https://doi.org/10.1038/s41467-017-02630-w

DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. / Luo, Na; Nixon, Mellissa J.; Gonzalez-Ericsson, Paula I.; Sanchez, Violeta; Opalenik, Susan R.; Li, Huili; Zahnow, Cynthia; Nickels, Michael L.; Liu, Fei; Tantawy, Mohammed N.; Sanders, Melinda E.; Manning, H. Charles; Balko, Justin M.

In: Nature Communications, Vol. 9, No. 1, 248, 01.12.2018.

Research output: Contribution to journalArticle

Luo, N, Nixon, MJ, Gonzalez-Ericsson, PI, Sanchez, V, Opalenik, SR, Li, H, Zahnow, C, Nickels, ML, Liu, F, Tantawy, MN, Sanders, ME, Manning, HC & Balko, JM 2018, 'DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer', Nature Communications, vol. 9, no. 1, 248. https://doi.org/10.1038/s41467-017-02630-w
Luo, Na ; Nixon, Mellissa J. ; Gonzalez-Ericsson, Paula I. ; Sanchez, Violeta ; Opalenik, Susan R. ; Li, Huili ; Zahnow, Cynthia ; Nickels, Michael L. ; Liu, Fei ; Tantawy, Mohammed N. ; Sanders, Melinda E. ; Manning, H. Charles ; Balko, Justin M. / DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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