EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells
EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells
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肺癌中 EGFR E746-A750 缺失通过外泌体介导的树突状细胞抑制来抑制抗肿瘤免疫
DOI：
10.1038/s41388-020-1182-y
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发表时间：
2020-01-30
期刊：
影响因子：
8
通讯作者：
Feng, Jifeng
中科院分区：
文献类型：
--
作者：
Yu, Shaorong;Sha, Huanhuan;Feng, Jifeng
EGFR突变型肺癌（LC）患者对PD-1/PD-L1阻断的反应较差。在缺乏独立基因验证的情况下，EGFR突变是否会扭曲宿主抗肿瘤免疫力尚不清楚。在这里，我们发现在临床上，具有E746-A750缺失突变（EGFR-19 del）的LC显示与肿瘤内CD 8 + T细胞的损失的时间关联。在异种移植模型中，表达EGFR-19 del的刘易斯肺癌（LLC）肿瘤在肿瘤发展的早期阶段具有低T细胞密度，沿着树突状细胞（DC）在肿瘤和引流淋巴结（LN）中表现出变异表型。重要的是，在荷瘤小鼠和LC患者的LN中观察到EGFR-19 del DC。LN内T细胞的增殖活性明显减弱。体外实验表明，DC的功能被EGFR-19 del LLC细胞通过外泌体摄取而抑制，其中来自EGFR-19 del LLC细胞的外泌体可以有效地将活性EGFR-19 del转移到DC的表面。注射EGFR-19 del肿瘤衍生的外泌体促进LLC肿瘤进展并诱导免疫抑制。吉非替尼和GM-CSF治疗的组合通过拯救DC的功能和增加抗PD-Ll治疗的功效来恢复EGFR-19 del肿瘤中的肿瘤T细胞浸润。总之，这些结果表明，具有EGFR E746-A750缺失突变的LC诱导无能DC通过外泌体抑制抗肿瘤免疫。
EGFR-mutant lung cancer (LC) patients display a poor response to PD-1/PD-L1 blockade. In the absence of independent genetic validation, whether EGFR mutation distorts host antitumor immunity is unknown. Here, we showed that in the clinic, LC with the E746-A750 deletion mutation (EGFR-19del) displayed a temporal association with the loss of intratumoral CD8+ T cells. In a xenograft model, EGFR-19del-expressing Lewis lung cancer (LLC) tumors had a low T cell density at the early stage of tumor development, along with dendritic cells (DCs) exhibiting variant phenotypes in the tumors and draining lymph nodes (LNs). Importantly, EGFR-19del DCs were observed in the LNs of tumor-bearing mice and LC patients. The proliferative activity of T cells within the LN was significantly dampened. In vitro experiments indicated that the function of DCs was repressed by EGFR-19del LLC cells through exosome uptake in which exosomes derived from the EGFR-19del LLC cells could efficiently transfer active EGFR-19del to the surface of the DCs. Injection of EGFR-19del tumor-derived exosomes promoted LLC tumor progression and induced immunosuppression. The combination of gefitinib and GM-CSF treatment recovered tumor T cell infiltration in EGFR-19del tumors by rescuing the function of DCs and increasing the efficacy of anti-PD-L1 treatment. Together, these results indicated that LC with the EGFR E746-A750 deletion mutation induced anergic DCs to repress antitumor immunity through exosomes.