Wang Yuan, Jia Zhenchang, Liang Chenxi, He Yunfei, Cong Min, Wu Qiuyao, Tian Pu, He Dasa, Miao Xiang, Sun Beibei, Yin Yue, Peng Chao, Yao Feng, Fu Da, Liang Yajun, Zhang Peiyuan, Xiong Hua, Hu Guohong
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
Cell Discov. 2023 Feb 21;9(1):20. doi: 10.1038/s41421-022-00507-x.
Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has shown durable clinical benefits in lung cancer. However, many patients respond poorly to ICB treatment, underscoring an incomplete understanding of PD-L1 regulation and therapy resistance. Here, we find that MTSS1 is downregulated in lung adenocarcinoma, leading to PD-L1 upregulation, impairment of CD8 lymphocyte function, and enhanced tumor progression. MTSS1 downregulation correlates with improved ICB efficacy in patients. Mechanistically, MTSS1 interacts with the E3 ligase AIP4 for PD-L1 monoubiquitination at Lysine 263, leading to PD-L1 endocytic sorting and lysosomal degradation. In addition, EGFR-KRAS signaling in lung adenocarcinoma suppresses MTSS1 and upregulates PD-L1. More importantly, combining AIP4-targeting via the clinical antidepressant drug clomipramine and ICB treatment improves therapy response and effectively suppresses the growth of ICB-resistant tumors in immunocompetent mice and humanized mice. Overall, our study discovers an MTSS1-AIP4 axis for PD-L1 monoubiquitination and reveals a potential combinatory therapy with antidepressants and ICB.
针对PD-1/PD-L1的免疫检查点阻断（ICB）疗法已在肺癌中显示出持久的临床益处。然而，许多患者对ICB治疗反应不佳，这突出表明对PD-L1调控和治疗耐药性的理解尚不完整。在此，我们发现MTSS1在肺腺癌中表达下调，导致PD-L1上调、CD8淋巴细胞功能受损以及肿瘤进展加速。MTSS1下调与患者ICB疗效改善相关。从机制上讲，MTSS1与E3连接酶AIP4相互作用，使PD-L1在赖氨酸263处发生单泛素化，导致PD-L1内吞分选和溶酶体降解。此外，肺腺癌中的EGFR-KRAS信号传导抑制MTSS1并上调PD-L1。更重要的是，通过临床抗抑郁药氯米帕明靶向AIP4并结合ICB治疗可改善治疗反应，并有效抑制免疫活性小鼠和人源化小鼠中ICB耐药肿瘤的生长。总体而言，我们的研究发现了一个用于PD-L1单泛素化的MTSS1-AIP4轴，并揭示了一种抗抑郁药与ICB的潜在联合疗法。
