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

Oncogene. 2020 Mar;39(13):2643-2657. doi: 10.1038/s41388-020-1182-y. Epub 2020 Jan 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / immunology*
  • Adenocarcinoma of Lung / pathology
  • Adenocarcinoma of Lung / therapy
  • Adult
  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • Cell Line, Tumor
  • Coculture Techniques
  • Dendritic Cells / immunology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / immunology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • Exosomes / metabolism
  • Female
  • Gefitinib / pharmacology
  • Gefitinib / therapeutic use
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use
  • Humans
  • Lung / immunology
  • Lung / pathology
  • Lung / surgery
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Male
  • Mice
  • Middle Aged
  • Pneumonectomy
  • Sequence Deletion
  • Tumor Escape / drug effects
  • Tumor Escape / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib