Abstract B290: Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.

Abstract

Abstract The recent clinical success of therapeutic blockade of the immune checkpoint Programmed Death (PD)-1 in advanced lung cancer patients suggests that mechanisms of immune escape may contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a gene signature indicative of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4) and multiple tumor-promoting inflammatory cytokines. Accordingly, we identified a decrease in the number of cytotoxic T cells and an increase in markers of T cell exhaustion in genetically engineered mouse models (GEMMs) of EGFR-driven lung cancer. PD-1 antibody blockade significantly improved the survival of mice with EGFR-driven lung adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor promoting cytokines. Expression of mutant EGFR in human bronchial epithelial cells induced PD-L1 expression, and PD-L1 expression was reduced by treatment with EGFR tyrosine kinase inhibitors (TKIs) in human non-small cell lung cancer (NSCLC) cell lines with an activated EGFR pathway. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, in addition to established effects on cell proliferation, and mechanistically link treatment response to PD-1 inhibition. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B290. Citation Format: Esra A. Akbay, Shohei Koyama, Julian Carretero, Abigail Altabef, Jeremy Tchaicha, Camilla Christensen, Takeshi Shimamura, Lynette Sholl, Scott Rodig, Gordon Freeman, Peter Hammerman, Glenn Dranoff, Kwok-Kin Wong. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B290.