Research ArticleCANCER IMMUNOLOGY

Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non–small cell lung cancer

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Science Immunology  31 Jan 2020:
Vol. 5, Issue 43, eaav3937
DOI: 10.1126/sciimmunol.aav3937

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Giving anti–PD-1 a boost

Anti–PD-1 therapy is ineffective in the context of EGFR-mutated lung adenocarcinomas (LUADs). Here, Sugiyama et al. find that these tumors have an immunosuppressive tumor microenvironment characterized by increased infiltration of regulatory T cells. Using a mouse model, they demonstrate that a clinically available EGFR inhibitor, erlotinib, can be used to improve responsiveness to anti–PD-1 therapy in EGFR-mutated LUADs. Because both anti–PD-1 antibodies and erlotinib are already being used in the clinic, this preclinical proof-of-concept study should serve as a basis for clinical studies to examine whether erlotinib enhances responsiveness of EGFR-mutated lung adenocarcinomas to PD-1–centric therapies.

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.

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