Met amplification attenuates lung tumor response to immunotherapy by inhibiting sting

Yong Zhang, Qifan Yang, Xiangyu Zeng, Manxiang Wang, Shuang Dong, Bin Yang, Xinyi Tu, Ting Wei, Wenzhuan Xie, Chao Zhang, Qiang Guo, Jake A. Kloeber, Yueyu Cao, Guijie Guo, Qin Zhou, Fei Zhao, Jinzhou Huang, Li Liu, Kai Zhang, Mingwei WangPing Yin, Kuntian Luo, Min Deng, Wootae Kim, Jing Hou, Yu Shi, Qian Zhu, Lifeng Chen, Sheng Hu, Junqiu Yue, Guoliang Pi, Zhenkun Lou

Research output: Contribution to journalArticlepeer-review


Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep singlecell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. Significance: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistantrelated MET amplification.

Original languageEnglish (US)
Pages (from-to)2726-2737
Number of pages12
JournalCancer discovery
Issue number11
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Oncology


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