RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer
Peng Deng, … , Xiaojun Xia, Jing Tan
Peng Deng, … , Xiaojun Xia, Jing Tan
Published October 6, 2022
Citation Information: J Clin Invest. 2022;132(22):e159628. https://doi.org/10.1172/JCI159628.
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Research Article Immunology Oncology

RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer

Abstract

Prevalent copy number alteration is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immune response in OV. Through interrogating the RAD21-regulated transcriptional program, we found that RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti–PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Our study identifies a RAD21–YAP/TEAD4–NuRD corepressor complex in immune modulation, and thus provides a potential target and biomarker for precision immunotherapy in OV.

Authors

Peng Deng, Zining Wang, Jinghong Chen, Shini Liu, Xiaosai Yao, Shaoyan Liu, Lizhen Liu, Zhaoliang Yu, Yulin Huang, Zhongtang Xiong, Rong Xiao, Jiuping Gao, Weiting Liang, Jieping Chen, Hui Liu, Jing Han Hong, Jason Yongsheng Chan, Peiyong Guan, Jianfeng Chen, Yali Wang, Jiaxin Yin, Jundong Li, Min Zheng, Chao Zhang, Penghui Zhou, Tiebang Kang, Bin Tean Teh, Qiang Yu, Zhixiang Zuo, Qingping Jiang, Jihong Liu, Ying Xiong, Xiaojun Xia, Jing Tan

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Figure 6

RAD21 suppresses antitumor immunity in vivo.

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RAD21 suppresses antitumor immunity in vivo. (A) Tumor volume and tumor ...
(A) Tumor volume and tumor weight over time in C57BL/6 mice implanted with Rad21-KO and control B16-OVA mouse cells. Data are shown as mean ± SEM (2-way ANOVA) for tumor volume and as mean ± SD (2-tailed t test) for tumor weight (n = 6 mice per group). (B and C) Tumor volume in nude mice (n = 8 mice per group) (B) and C57BL/6 mice (n = 6 mice per group) (C) implanted with Rad21-KO and control B16-OVA mouse cells. Mice were pretreated with CD8-depleting antibodies at –1, 2, and 5 days. Data are shown as mean ± SEM (2-way ANOVA). (D and E) Flow cytometry analysis showing the numbers of tumor-infiltrating CD8+ T cells (D) and expression of activation marker CD69 and effector molecules IFN-γ and GZMB (E) in CD8+ T cells. Data are shown as mean ± SD (n = 5, 2-tailed t test). (F) Mice with established Rad21-KO and control B16-OVA tumors were treated with anti–PD-1 at indicated time points. Tumor volume and survival rates are shown. Data are shown as mean ± SEM (2-way ANOVA). (G) Representative bioluminescence images of mice with established Rad21-KO and control ID8 tumors treated with anti–PD-1 formed by intraperitoneal injection at day 9 and day 12. (H) The bar graph shows the change in bioluminescence in mice. Data are shown as mean ± SEM (1-way ANOVA). (I and J) Flow cytometry analysis showing the numbers of tumor-infiltrating CD8+ T cells (I) and expression of CD69 and effector molecules IFN-γ and GZMB (J). Data are shown as mean ± SD (2-tailed t test). **P < 0.01; ***P < 0.001.