MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING
MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING
复制标题
MET 扩增通过抑制 STING 减弱肺肿瘤对免疫治疗的反应
DOI：
10.1158/2159-8290.cd-20-1500
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发表时间：
2021-11-01
期刊：
影响因子：
28.2
通讯作者：
Lou, Zhenkun
中科院分区：
文献类型：
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作者：
Zhang, Yong;Yang, Qifan;Lou, Zhenkun
免疫检查点阻断(ICB)使癌症治疗发生了革命性的变化。然而，患者对ICB的反应很难预测。在这里，我们检查了81例接受ICB治疗的肺癌患者，发现MET扩增的患者对ICB耐药，无进展生存较差。MET扩增的肿瘤显著降低了刺激性水平和抗肿瘤T细胞的浸润。此外，我们对20,000多个单个免疫细胞进行了深入的单细胞RNA测序，发现在MET扩增患者中，XIST和CD96阳性的耗尽自然杀伤(NK)细胞亚群增加，CD8(+)T细胞和NK细胞数量减少，这是一个免疫抑制特征。从机制上讲，我们发现癌基因MET信号诱导UPF1的磷酸化，并通过调节UPF1的3‘-UTR长度下调肿瘤细胞STING的表达。MET扩增引起的ICB效率下降可以通过抑制MET来克服。迹象：我们认为MET抑制剂与ICB联合使用可以克服MET扩增引起的ICB耐药性。我们的报告揭示了急需的信息，这些信息将有助于原发性MET扩增或EGFR酪氨酸激酶抑制剂耐药相关MET扩增患者的治疗。
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.