2. Academic Validation
  3. MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation

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.
Yuan Wang 1,  Zhenchang Jia 1,  Chenxi Liang 1,  Yunfei He 1,  Min Cong 1,  Qiuyao Wu 1,  Pu Tian 1,  Dasa He 1,  Xiang Miao 1,  Beibei Sun 2,  Yue Yin 3,  Chao Peng 3,  Feng Yao 2,  Da Fu 4 5,  Yajun Liang 1,  Peiyuan Zhang 6,  Hua Xiong 7,  Guohong Hu 8
Affiliations

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.
PMID: 36810288 DOI: 10.1038/s41421-022-00507-x
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.

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