Research ArticleCANCER IMMUNOLOGY

Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity

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Science Immunology  09 Aug 2019:
Vol. 4, Issue 38, eaav6473
DOI: 10.1126/sciimmunol.aav6473

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Enhanced inhibitor

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) block oncogenic receptor signaling and are used as a first-line treatment for EGFR-mutated non–small cell lung cancer. Resistance to EGFR TKIs, including the standard hyperfractionated EGFR TKI (HyperTKI) treatment, is a problem that has driven the development of next-generation inhibitors. Here, Liu et al. describe the improved efficacy of hypofractionated EGFR TKI (HypoTKI) relative to HyperTKI in triggering antitumor T cell responses and preventing relapse in a TKI-sensitive syngeneic murine tumor model through a mechanism involving the type I IFN and MyD88 signaling pathways. Coadministration of HypoTKI with an anti–PD-L1 antibody further improved antitumor responses and reduced tumor relapse, thus suggesting that this combined therapy may be a potential alternative to existing treatment regimens.

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non–small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand–1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.

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