MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation

Yuan Wang; Zhenchang Jia; Chenxi Liang; Yunfei He; Min Cong; Qiuyao Wu; Pu Tian; Dasa He; Xiang Miao; Beibei Sun; Yue Yin; Chao Peng; Feng Yao; Da Fu; Yajun Liang; Peiyuan Zhang; Hua Xiong; Guohong Hu

doi:10.1038/s41421-022-00507-x

MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation

Cell Discov. 2023 Feb 21;9(1):20. doi: 10.1038/s41421-022-00507-x.

Authors

Yuan Wang¹, Zhenchang Jia¹, Chenxi Liang¹, Yunfei He¹, Min Cong¹, Qiuyao Wu¹, Pu Tian¹, Dasa He¹, Xiang Miao¹, Beibei Sun², Yue Yin³, Chao Peng³, Feng Yao², Da Fu^{4

5}, Yajun Liang¹, Peiyuan Zhang⁶, Hua Xiong⁷, Guohong Hu⁸

Affiliations

¹ Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
² Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
³ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China.
⁴ Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ General Surgery, Ruijin Hospital & Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁶ Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. zhangpeiyuan@sinh.ac.cn.
⁷ Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China. cnhxiong@163.com.
⁸ Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. ghhu@sinh.ac.cn.

Abstract

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.