Abstract 5302: Overcoming cancer immune evasion in lung carcinoma using EGFR-TKI (Gefitinib)

Abstract

Abstract Clinical studies for immunotherapy targeting various types of carcinoma, including lung carcinoma, are currently underway, yet the clinical effectiveness of these therapies is very limited. Recent findings demonstrate that cancer immune evasion is a major contributing factor to this problem. Cancer cells produce a variety of immunosuppressive molecules that inhibit the host cell's immune response, leading to conditions such as cachexia that decrease patients’ quality of life. EGFR mutations in lung carcinoma are known to lead to processes characteristic of malignancies, such as cell cycle progression, metastasis, and angiogenesis. Based on these observations, we tested the hypothesis that EGFR activation leads to immune evasion by cancer cells via the production of various immunosuppressive molecules. In this study, 6 lung adenocarcinoma cell lines were used, namely A549, RELF-LC-OK, PC-9, HCC-827, NCI-H1650, and NCI-H1975. We demonstrate that these cells secrete immunosuppressive cytokines such as IL-6, TGF-beta and VEGF, which inhibit the maturation of dendritic cells and prevent them to activate T cells. Then, we show that Gefitinib administration at sub-lethal concentration inhibits the production of immunosuppressive cytokines in EGFR-TKI sensitive PC-9 and HCC-827 cells those with EGFR mutations as well as in EGFR-TKI resistant NCI-H1650 cells that have an EGFR mutation but lack the PTEN gene. While, cytokine production is not inhibited by Gefitinib in A549 and RELF-LC-OK cells with wild type EGFR genes and NCI-H1975 cells that have both EGFR-TKI sensitive and resisitant mutations. Additionally, EGFR-TKI administration in PC-9, HCC827, and NCI-H1650 cells restores dendritic cell function, which was initially reduced by the supernatant of tumor cells. These results show that lung adenocaricinoma harboring EGFR mutations evade immune response through secreteting immunosuppressive agents and that the immune response is restored by Gefitinib administration. Thus, the combination of Gefitinib and immunotherapy may have synergistic effect and will be a promising treatment of lung cancer patients harboring EGFR mutation, including certain population of EGFR-TKI resistant cases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5302.