RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity

Zhuo Zhang, Lin Luo, Chuan Xing, Yu Chen, Peng Xu, Mao Li, Ling Zeng, Chao Li, Sadashib Ghosh, Deborah Della Manna, Tim Townes, William J. Britt, Narendra Wajapeyee, Barry P. Sleckman, Zechen Chong, Jianmei Wu Leavenworth, Eddy S. Yang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Expanding the utility of immune-based cancer treatments is a clinical challenge due to tumor-intrinsic factors that suppress the immune response. Here we report the identification of tumoral ring finger protein 2 (RNF2), the core subunit of polycomb repressor complex 1, as a negative regulator of antitumor immunity in various human cancers, including breast cancer. In syngeneic murine models of triple-negative breast cancer, we found that deleting genes encoding the polycomb repressor complex 1 subunits Rnf2, BMI1 proto-oncogene, polycomb ring finger (Bmi1), or the downstream effector of Rnf2, remodeling and spacing factor 1 (Rsf1), was sufficient by itself to induce durable tumor rejection and establish immune memory by enhancing infiltration and activation of natural killer and CD4+ T cells, but not CD8+ T cells, into the tumor and enabled their cooperativity. These findings uncover an epigenetic reprogramming of the tumor-immune microenvironment, which fosters durable antitumor immunity and memory.

Original languageEnglish
Pages (from-to)1018-1038
Number of pages21
JournalNature Cancer
Volume2
Issue number10
DOIs
StatePublished - Oct 2021

Bibliographical note

Funding Information:
E.S.Y. is a consultant for AstraZeneca, Eli Lilly and Company and is on the Advisory Board for Bayer Pharmaceuticals, AstraZeneca, Clovis Oncology and Strata Oncology. The research in the laboratory of E.S.Y. is supported by funding from Novartis International AG, Eli Lilly and Company, Clovis Oncology and the American Society of Clinical Oncology. The remaining authors declare no competing interests.

Funding Information:
We thank L. Z. Shi and H. Wang for helpful discussion on this project. We are grateful to H. Shen and S. Bugide for technical assistance. E.S.Y. is a ROAR Southeast Cancer Foundation Endowed Chair. This work was supported by grants from Autotech LLC (to E.S.Y.), from Breast Cancer Research Foundation of Alabama (to E.S.Y.), from American Association for Cancer Research/Triple Negative Breast Cancer Foundation (15-20-43-YANG) (to E.S.Y.), and from start-up funds from UAB (to J.W.L.). J.W.L. is also supported by the DoD PRCRP Career Award (W81XWH-18-1-0315) and National Institutes of Health (NIH) R01AI148711. N.W. is supported by the DoD grant W81XWH-19-1-0084. We also thank V. S. Hanumanthu from the Comprehensive Flow Cytometry Core as well as the UAB Small Animal Imaging Shared Facility (supported by the O'Neal Comprehensive Cancer Center (NIH P30 CA013148) and funding to Rheumatic Diseases Core Center/Center for AIDS Research (NIH P30 AR048311/NIH P30 AI27667).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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