Fifteen percent of lung adenocarcinomas harbor mutations in the Epidermal Growth Factor Receptor (EGFR). Although EGFR mutant tumors show sensitivity to specific tyrosine kinase inhibitors (TKIs) like erlotinib, resistance develops after an average of 12 months and there are currently no approved therapeutic strategies to overcome resistance. Therefore, novel approaches to delay resistance and improve patient survival are crucial. Recent discoveries in tumor immunology have revealed the potential of immune-based therapies to treat lung malignancies. In particular, immune checkpoint inhibitors such as anti-PD-1 have shown efficacy in a subset of patients with metastatic lung adenocarcinoma with minimal toxicity. These promising data led us to investigate the benefit of immune modulatory agents in EGFR mutant lung cancer. As a first step, we set out to explore the role of the immune system in this lung adenocarcinoma subset using a tetracycline-inducible mouse model of EGFR mutant lung cancer. We found, in these models, that lung-specific expression of mutant EGFR and consequent tumor formation leads to the establishment of an immunosuppressive tumor microenvironment characterized by an overall decrease in CD4 T cells, infiltration of Tregs, up-regulation of PD-1 expression on both helper and cytotoxic T cells and a diminished cytokine production by these T cells. Additionally, by flow cytometry and quantitative PCR of FACS-sorted cells, we have observed increased expression of PD-L1 on alveolar macrophages, which represent over 60% of the CD45+ cells in these tumors, suggesting an engagement of the adaptive and innate arms of the immune system to mediate immunosuppression via the PD-1/PD-L1 axis. Furthermore, when the tumor suppressor gene p53 was deleted, we observed a marked decrease in tumor infiltrating CD8 T cells when compared to p53 wild-type tumors. Currently, we are evaluating the functional role of elements of the immune system in these models to delineate their effects on tumor progression and therapeutic response. Moreover, we are investigating whether the observed immunosuppression in these tumors can be altered by immunomodulatory agents such as the anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors alone or in combination with EGFR TKIs.
Citation Format: Deborah Ayeni, Ping-Chih Ho, Curtis Perry, Susan Kaech, Katerina Politi. Modulation of the immune system as a strategy to treat EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A083.
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