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

Oncogene volume 39, pages 2643–2657 (2020)Cite this article

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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.

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Fig. 1: Immunological features of LC tumors were distinct in terms of size and EGFR genotype.
Fig. 2: EGFR-19del LLC tumors showed a dramatic loss of CD8+ T cells.
Fig. 3: EGFR-19del LLC tumors altered the phenotype and function of DCs in the tumor and LN.
Fig. 4: DCs within draining lymph nodes lost their ability to perform CD8+ T cell priming and harbored the EGFR mutation.
Fig. 5: EGFR-mutant LC cells dampened the function and maturation of DCs by secreting exosomes in vitro.
Fig. 6: Exosomes derived from EGFR-mutant LLC cells accelerated tumor growth and immunosuppression.
Fig. 7: Combination GM-CSF and EGFR-TKI treatment restored antitumor immunity and enhanced the efficacy of immunotherapy in EGFR-19del LLC tumor-bearing mice.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81871873); the Project of Invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Youth Talent (QNRC2016646); the China Postdoctoral Science Foundation (2017M621680); the Six talent peaks project in Jiangsu Province (WSN-039); and the talents program of Jiangsu Cancer Hospital (YC201807).

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Authors and Affiliations

  1. Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China

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

  2. Department of Medical Oncology, Affiliated Hospital of Xuzhou Medical University, XuZhou, Jiangsu, China

    Xiaobing Qin

  3. Department of Pathology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China

    Yan Chen

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Yu, S., Sha, H., Qin, X. et al. EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells. Oncogene 39, 2643–2657 (2020). https://doi.org/10.1038/s41388-020-1182-y

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