Abstract 278: High levels of expression of the transcription factor Brachyury induce resistance of human carcinoma cells to immune-mediated attack. (2013)

Abstract The phenomenon of epithelial-mesenchymal transition (EMT) is recognized as a relevant process during the progression of carcinomas. EMT is a phenotypic switch that allows epithelial tumor cells to acquire features of mesenchymal cells, including the ability to migrate and invade and, therefore, to disseminate from the primary site. In addition to promoting tumor dissemination, various reports have demonstrated that acquisition of features of EMT associates with tumor resistance to the cytotoxic effects of chemotherapy, radiation, and some targeted therapies. Presently, no studies have been conducted to thoroughly investigate whether this phenotypic switch may also contribute to the escape of tumors from host immune-surveillance and immune-mediated rejection. Our laboratory has characterized the T-box transcription factor Brachyury as a tumor-associated antigen and a regulator of EMT in human carcinomas. Currently, a Brachyury-based, recombinant yeast cancer vaccine is ongoing Phase I clinical testing for the treatment of patients with advanced carcinomas. Work in our laboratory has demonstrated that high levels of Brachyury expression in human carcinoma cell lines is associated with increased resistance to both chemo- and radiation therapies. In the present study, human epithelial carcinoma cell lines undergoing EMT via Brachyury over-expression and their epithelial tumor cell counterparts were comparatively utilized to evaluate whether EMT imparts resistance to immune-mediated attack. Our results demonstrate a bell-shaped relationship between the levels of Brachyury expression and the susceptibility of human carcinoma cell lines to lysis by immune cells. While tumor cells with low/intermediate levels of Brachyury expression are vulnerable to cell lysis, those with high levels of Brachyury expression are very resistant to lysis by immune cells. Our results demonstrate that a high level of Brachyury expression in human tumor cells reduces their susceptibility to antigen-specific CD8+ cytotoxic T cells and innate, natural killer (NK) and lymphokine-activated killer (LAK) cells. While the mechanisms involved in this phenomenon are currently under investigation in our laboratory, preliminary studies suggest that antigen processing and/or presentation is not responsible for the defective immune-mediated cytotoxicity of EMT-tumors. Altogether our results indicate that targeting the process of EMT may be a successful strategy not only to interfere with tumor dissemination but also to increase the effectiveness of immunotherapeutic interventions against metastatic tumors. Citation Format: Duane H. Hamilton, Bruce Huang, Romaine I. Fernando, Kwong-Yok Tsang, Claudia M. Palena. High levels of expression of the transcription factor Brachyury induce resistance of human carcinoma cells to immune-mediated attack. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 278. doi:10.1158/1538-7445.AM2013-278