Journal Article

EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells

Li, Xiaoyou, Feng Jifeng, Qin Xiaobing, Sha Huanhuan, Chen, Yan, Shi Meiqi, Yu, Shaorong

2020

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Anergy / CD8 antigen / Cell density / Dendritic cells / Developmental stages / Epidermal growth factor receptors / Exosomes / Gefitinib / Gene deletion / Granulocyte-macrophage colony-stimulating factor / Immunity / Immunosuppression / Inhibitor drugs / Lung cancer / Lymph nodes / Lymphocytes T / Metastases / Mutants / Mutation / PD-1 protein / PD-L1 protein / Phenotypes / Tumors / Xenografts