Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
Abstract The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of m…
Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade
Abstract Introduction Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses. Methods We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional Kras G12D and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD-1) or IL-6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors. Results Tumors in IL-17:Kras…
Abstract B290: Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
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 lu…