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 5

RAD21 ablation induces T cell activation in vitro.

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RAD21 ablation induces T cell activation in vitro. (A and B) qRT-PCR val...
(A and B) qRT-PCR validation of representative ISGs Ifi44, Ddx58, Ifit3, and Isg15 in Rad21-KD or Rad21-overexpressed and control ID8 cells and B16-OVA cells in the presence or absence of IFN-β treatment. (C and D) Expression levels of MHC-I and MHC-I–SIINFEKL on Rad21-KD and control ID8-OVA and B16-OVA cells in the presence or absence of IFN-β treatment were determined by FACS. (E–I) Rad21-KD and control ID8-OVA and B16-OVA cells were treated with vehicle or IFN-β and then cocultured with B3Z cells or OT-I cells, after which B3Z activation was determined by LacZ activity (E) and OT-I activation was determined by secretion of IL-2 (F) and IFN-γ (G) and expression of effector molecules GZMB (H) and IFN-γ (I). (J and K) The cytotoxic effect of OT-I was measured by annexin V/propidium iodide staining (J) and LDH release (K) of ID8-OVA and B16-OVA cells after coculture with OT-I for 48 hours. Data in A–K are shown as mean ± SD (n = 3, 2-tailed t test). *P < 0.05; **P < 0.01; ***P < 0.001.