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
  • 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. [email protected].
  • 7. Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 8. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
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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