Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR -mutated non–small cell lung cancer
Open Access
- 3 January 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 5 (43)
- https://doi.org/10.1126/sciimmunol.aav3937
Abstract
The clinical efficacy of anti–PD-1 (programmed cell death–1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor (EGFR)–mutated lung adenocarcinomas, for which anti–PD-1 mAb is largely ineffective. Whereas EGFR-mutated lung adenocarcinomas had a noninflamed TME, CD4+ effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration. The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor–1; the former increased CCL22, which recruits CD4+ regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8+ T cell infiltration. The EGFR inhibitor erlotinib decreased CD4+ effector regulatory T cells infiltration in the TME and in combination with anti–PD-1 mAb showed better antitumor effects than either treatment alone. Our results suggest that EGFR inhibitors when used in conjunction with anti–PD-1 mAb could increase the efficacy of immunotherapy in lung adenocarcinomas.Keywords
Funding Information
- Naito Foundation
- Naito Foundation
- National Cancer Center (28-A-7)
- Japan Agency for Medical Research and Development (P-CREATE, no. 16cm0106301h0002)
- Japan Society for the Promotion of Science (17H06162)
- Japan Society for the Promotion of Science (17J09900)
- Ono Pharmaceutical
- Novartis Research Grant
- Takeda Foundation
- Japan Society for the Promotion of Science (17K18388)
- Kobayashi Foundation for Cancer Research
- SGH Foundation
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