Zhang Yangyang, Zeng Lingxiu, Wang Meng, Yang Zhenwei, Zhang Hailin, Gao Liping, Zhang Ranran, Liu Jialong, Shan Wenqing, Chang Ying, Liu Lan, Zhao Qiu, Li Yong, Liu Jing
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China
J Immunother Cancer. 2023 Sep;11(9). doi: 10.1136/jitc-2023-007313.
Colon cancer is one of the most prevalent cancers and exhibits high mortality worldwide. Despite the certain success in the immunotherapy of many tumor types, the limited response of colon cancer to immunotherapy remains a difficult problem. Retinoic acid-inducible gene-I (RIG-I) is a crucial component in innate antiviral immunity, but its role in antitumor immunity remains unclear. Here, in this report, we found that silencing RIG-I decreased resistance to tumor cells killed by T cells and attenuated colon tumor growth in immunocompetent mice. Meanwhile, overexpressing RIG-I promoted tumor progression, and high expression of RIG-I sensitized cells to anti-programmed cell death protein-1 (PD-1) therapy in vivo. Interestingly, we found that RIG-I influenced programmed cell death ligand 1 (PD-L1) expression to promote colon cancer immune evasion without relying on type I interferon stimulation. Mechanistically, RIG-I could compete with Speckle Type POZ protein (SPOP) to bind PD-L1, leading to attenuation of the polyubiquitination and proteasomal degradation of PD-L1. Collectively, our work reveals new insights into the contribution of RIG-I to driving immune evasion by maintaining the stability of PD-L1 through post-translational modification and provides a promising biomarker of the efficacy of immunotherapy in colon cancer.
结肠癌是最常见的癌症之一，在全球范围内具有较高的死亡率。尽管在许多肿瘤类型的免疫治疗方面取得了一定成功，但结肠癌对免疫治疗的有限反应仍然是一个难题。视黄酸诱导基因-I（RIG-I）是天然抗病毒免疫的关键组成部分，但其在抗肿瘤免疫中的作用仍不清楚。在此报告中，我们发现沉默RIG-I会降低免疫活性小鼠对T细胞杀伤肿瘤细胞的抗性，并减弱结肠肿瘤生长。同时，过表达RIG-I会促进肿瘤进展，并且RIG-I的高表达会使体内细胞对抗程序性细胞死亡蛋白-1（PD-1）治疗敏感。有趣的是，我们发现RIG-I影响程序性细胞死亡配体1（PD-L1）的表达，以促进结肠癌免疫逃逸，而不依赖于I型干扰素刺激。从机制上讲，RIG-I可以与斑点型POZ蛋白（SPOP）竞争结合PD-L1，导致PD-L1的多聚泛素化和蛋白酶体降解减弱。总体而言，我们的工作揭示了RIG-I通过翻译后修饰维持PD-L1稳定性对驱动免疫逃逸的贡献的新见解，并为结肠癌免疫治疗疗效提供了一个有前景的生物标志物。
