PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer.

Abstract

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell-mediated immunity at the tumor site.

• Authors: Nisha Nagarsheth, Dongjun Peng, Ilona Kryczek, Ke Wu, Wei Li, Ende Zhao, Lili Zhao, Shuang Wei, Timothy Frankel, Linda Vatan, Wojciech Szeliga, Yali Dou, Scott Owens, Victor Marquez, Kaixiong Tao, Emina Huang, Guobin Wang, Weiping Zou
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 2 Pg. 275-82 (Jan 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26567139 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Chemokines
• Polycomb Repressive Complex 2

Topics

• Cell Movement (genetics, immunology)
• Cell Proliferation (genetics)
• Chemokines (immunology)
• Colonic Neoplasms (genetics, immunology, pathology)
• Epigenesis, Genetic
• Humans
• Polycomb Repressive Complex 2 (genetics, immunology)
• T-Lymphocytes (immunology, metabolism)
• Th1 Cells (immunology, metabolism)
• Transfection