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

doi:10.1038/s43018-021-00263-z

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 journal › Article › peer-review

14 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 language	English
Pages (from-to)	1018-1038
Number of pages	21
Journal	Nature Cancer
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s43018-021-00263-z
State	Published - Oct 2021

Bibliographical note

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

Funding

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. 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).

Funders	Funder number
American Association for Cancer Research/Triple Negative Breast Cancer Foundation	15-20-43-YANG
Autotech LLC
O'Neal Comprehensive Cancer Center	P30 CA013148
Rheumatic Diseases Core Center/Center for AIDS Research	P30 AR048311/NIH P30 AI27667
National Institutes of Health (NIH)	R01AI148711
National Institutes of Health (NIH)
U.S. Department of Defense	W81XWH-19-1-0084, W81XWH-18-1-0315
U.S. Department of Defense
American Association for Cancer Research
Eli Lilly and Company
Novartis
American Society of Clinical Oncology
University of Alabama, Birmingham
Clovis Oncology
Breast Cancer Research Foundation of Alabama

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s43018-021-00263-z

Cite this

Zhang, Z., Luo, L., Xing, C., Chen, Y., Xu, P., Li, M., Zeng, L., Li, C., Ghosh, S., Della Manna, D., Townes, T., Britt, W. J., Wajapeyee, N., Sleckman, B. P., Chong, Z., Leavenworth, J. W., & Yang, E. S. (2021). RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4⁺ T-cell-dependent antitumor immunity. Nature Cancer, 2(10), 1018-1038. https://doi.org/10.1038/s43018-021-00263-z

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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.",

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Zhang, Z, Luo, L, Xing, C, Chen, Y, Xu, P, Li, M, Zeng, L, Li, C, Ghosh, S, Della Manna, D, Townes, T, Britt, WJ, Wajapeyee, N, Sleckman, BP, Chong, Z, Leavenworth, JW & Yang, ES 2021, 'RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4⁺ T-cell-dependent antitumor immunity', Nature Cancer, vol. 2, no. 10, pp. 1018-1038. https://doi.org/10.1038/s43018-021-00263-z

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