Abstract A64: Brachyury-mediated epithelial-mesenchymal transition of human carcinoma cells is associated with an increased resistance to immune-mediated attack

Abstract

Abstract The epithelial-mesenchymal transition (EMT) has recently been recognized as a relevant process during the progression of carcinomas. Epithelial tumor cells undergoing EMT have been shown to acquire a mesenchymal-like phenotype, cell motility, and invasiveness, in vivo metastatic propensity and stem cell-like properties, including the ability to resist cell death initiated by traditional cancer treatment modalities such as chemotherapy and radiation. The development of therapeutic interventions aimed at interfering with EMT is therefore emerging as a rational approach for the prevention of cancer metastasis and alleviation of therapeutic resistance. Promising results recently obtained in preclinical and clinical studies with cancer vaccines may lead to their use for the treatment of various types of cancer; the concept of utilizing a vaccine to specifically target essential regulators of EMT is yet to be exploited in the field of tumor immunology. Recently, we have demonstrated that Brachyury, a T-box transcription factor essential for embryonic development, plays a central role in the induction of EMT in human carcinoma cells. In contrast to other drivers of EMT, Brachyury is highly expressed in various types of human tumors, while its expression in most normal adult tissues is undetectable. Moreover, Brachyury-specific T cells capable of lysing human tumor cell lines in an antigen-specific, HLA-restricted manner can be expanded from the peripheral blood of cancer patients, making Brachyury an attractive target for a vaccination strategy designed to specifically target cells undergoing an EMT. In light of the documented resistance of mesenchymal-like tumor cells to chemotherapy and radiation, we have thoroughly investigated the susceptibility of tumor cells undergoing EMT to immune-mediated attack. Utilizing several epithelial human tumor cell lines stably transfected to express various levels of Brachyury, we have observed that tumor cells with low to moderate amounts of Brachyury can be efficiently lysed by various immune-mediated mechanisms, while very high levels of Brachyury expression correlate with increased resistance to lysis mediated by natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and antigen-specific CD8+ T cells. It has been suggested that EMT is a reversible process, whereby cells can undergo a mesenchymal-epithelial transition (MET). By stably inhibiting the expression of Brachyury in various mesenchymal-like human tumor cell lines, we have also demonstrated that induction of MET restores susceptibility of tumor cells to immune-mediated attack. Currently, the mechanisms responsible for the acquisition of increased resistance to immune-mediated killing by cells undergoing an EMT are being investigated. The results from these studies will be fundamental in designing strategies aimed at rendering metastatic carcinoma cells more susceptible not only to chemotherapy and radiation, but also to immunotherapeutic interventions against the tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A64.