Lin Yanxun, Jin Huan, She Yong, Zhang Yiqun, Cui Lei, Xie Chunyuan, Liu Yongxiang, Zhang Huanling, Guo Hui, Wu Jiaxin, Li Lin, Guo Zixuan, Wang Xiaojuan, Jiang Wu, Chen Xu, He Shuai, Zhou Penghui, Tan Jing, Bei Jin-Xin, Liu Jinyun, Chen Yan-Xing, Zhao Qi, Xia Xiaojun, Wang Zining
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510050, China.
Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Proc Natl Acad Sci U S A. 2025 Feb 4;122(5):e2417529122. doi: 10.1073/pnas.2417529122. Epub 2025 Jan 30.
Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models. By analysis of the CBX2-regulated transcriptional program coupled with mass spectrometry screening of CBX2-interacting proteins, we found that CBX2 suppresses interferon signaling independent of its function in the canonical PRC. Mechanistically, CBX2 directly interacts with RACK1 and facilitates the recruitment of HDAC1, which attenuates the H3K27ac modification on the promoter regions of interferon-stimulated genes, thereby suppressing interferon signaling. Consequently, CBX2 reduces tumor immunogenicity and enables immune evasion. Moreover, a high expression level of CBX2 is associated with immune suppressive tumor microenvironment and reduced efficacy of immunotherapy across various human cancer types. Our study identifies a noncanonical CBX2-RACK1-HDAC1 corepressor complex in suppression of tumor immunogenicity, thereby presenting a potential target and biomarker for tumor immunotherapy.
染色质盒蛋白2（CBX2）是多梳抑制复合物（PRC）的关键组成部分，与多种人类癌症的发生发展有关。然而，其在肿瘤免疫原性调节和免疫逃逸中的作用仍未得到充分了解。在本研究中，我们利用小鼠同基因肿瘤模型发现，敲除CBX2可导致肿瘤生长抑制、肿瘤免疫微环境激活，并增强抗PD1或过继性T细胞疗法的治疗效果。通过分析CBX2调控的转录程序并结合对CBX2相互作用蛋白的质谱筛选，我们发现CBX2独立于其在经典PRC中的功能抑制干扰素信号传导。机制上，CBX2直接与RACK1相互作用并促进HDAC1的募集，从而减弱干扰素刺激基因启动子区域的H3K27ac修饰，进而抑制干扰素信号传导。因此，CBX2降低肿瘤免疫原性并实现免疫逃逸。此外，CBX2的高表达水平与免疫抑制性肿瘤微环境以及多种人类癌症类型中免疫治疗疗效降低相关。我们的研究在抑制肿瘤免疫原性方面鉴定出一种非经典的CBX2-RACK1-HDAC1共抑制复合物，从而为肿瘤免疫治疗提供了一个潜在靶点和生物标志物。
