Weng Nuoqing, Zhou Chuzhou, Zhou Yuhang, Zhong Yanping, Jia Zhe, Rao Xionghui, Qiu Huaiyu, Zeng Guangyan, Jin Xinghan, Zhang Jianbao, Zhuang Zhehong, Liang Zhihao, Deng Yuan, Li Qinghai, Yang Shasha, Luo Huixing, Wang Huiyun, Wu Xiaobin
Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China.
Department of Gastroenterology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China.
Cancer Lett. 2024 Mar 1;584:216618. doi: 10.1016/j.canlet.2024.216618. Epub 2024 Jan 9.
As an immune checkpoint protein expressed by diverse cancer cells, programmed death ligand 1 (PD-L1) facilitates immune evasion by interacting with programmed cell death-1 (PD-1) on T cells. Despite the clinical benefits observed in various cancer types, strategies targeting PD-1/PD-L1 have demonstrated limited efficacy in gastric cancer (GC). Furthermore, the regulation of PD-L1, especially at post-translational modification levels, remains largely unknown. Therefore, it is crucial to elucidate the mechanisms governing PD-L1 expression to enhance anti-tumor immunity. In this study, we have identified that IKAROS family zinc finger 4 (IKZF4) and Non-POU domain-containing octamer-binding (NONO) synergistically regulate and enhance the expression of RAB11 family-interacting protein 3 (RAB11FIP3) in GC. The IKZF4/NONO-RAB11FIP3 axis facilitates the endosomal recycling of PD-L1, particularly on the cell membrane of GC cells. Moreover, overexpression of RAB11FIP3 mitigates the hypo-expression of PD-L1 protein resulting from IKZF4 or NONO deletion. Functionally, the silencing of RAB11FIP3 or IKZF4 promotes T cell proliferation, and enhances T-cell cytotoxicity towards GC cells in vitro, which further inhibits tumor immune evasion in mice via increasing the infiltration of CD8 T cells into the tumor microenvironment (TME) to suppress GC progression. Our study suggests that the IKZF4/NONO-RAB11FIP3 axis promotes immune evasion by facilitating PD-L1 endosome recycling, thus presenting a potential therapeutic target for GC treatment.
作为一种由多种癌细胞表达的免疫检查点蛋白，程序性死亡配体1（PD-L1）通过与T细胞上的程序性细胞死亡蛋白1（PD-1）相互作用来促进免疫逃逸。尽管在多种癌症类型中观察到了临床益处，但针对PD-1/PD-L1的策略在胃癌（GC）中的疗效有限。此外，PD-L1的调控，尤其是在翻译后修饰水平上的调控，在很大程度上仍不清楚。因此，阐明控制PD-L1表达的机制以增强抗肿瘤免疫力至关重要。在本研究中，我们发现IKAROS家族锌指蛋白4（IKZF4）和含非POU结构域的八聚体结合蛋白（NONO）协同调节并增强胃癌中RAB11家族相互作用蛋白3（RAB11FIP3）的表达。IKZF4/NONO-RAB11FIP3轴促进了PD-L1的内体循环，特别是在胃癌细胞的细胞膜上。此外，RAB11FIP3的过表达减轻了因IKZF4或NONO缺失导致的PD-L1蛋白低表达。在功能上，RAB11FIP3或IKZF4的沉默促进T细胞增殖，并在体外增强T细胞对胃癌细胞的细胞毒性，这通过增加CD8 T细胞向肿瘤微环境（TME）的浸润来进一步抑制小鼠肿瘤免疫逃逸，从而抑制胃癌进展。我们的研究表明，IKZF4/NONO-RAB11FIP3轴通过促进PD-L1内体循环来促进免疫逃逸，从而为胃癌治疗提供了一个潜在的治疗靶点。
