Abstract 5165: Cancer stem cells express specific immunogenic proteins that induce Th17-dominant immunity resulting in regression of parental tumor in vivo

Abstract

Abstract Cancer stem cells (CSCs), which are capable of self-renewal and asymmetrical cell division to initiate differentiated cancer cells and tumor tissues, have been identified in a number of human solid cancers. Although CSCs are a minority population, they play a critical role in metastasis and cancer recurrence and are resistant to classical anti-cancer treatment or molecular-targeting therapy. It seems that the altered activation and/or overexpression of ATP-binding cassette multidrug efflux transporters, anti-apoptotic factors, stem cell-specific growth signaling as well as relative dormancy contribute to the resistance. T cell-mediated immunotherapy has been demonstrated to mediate antitumor reactivity. The outcome of immune responses is dependent on the balance between effector T cells and regulatory T (Treg) cells that mediate peripheral tolerance. Interestingly, most of the identified immunogenic tumor antigens belong to the cancer/testis (CT) antigens, which are expressed in a variety of cancerous tissues and are silent in normal differentiated cells, with the exception of the testis, ovary, and trophoblast. Since Treg cells are maintained with antigen stimulation by dendritic cells (DCs) that acquire dying cells at steady state, CT antigens are unlikely to maintain peripheral tolerance, owing to their restricted expression in the testis and malignant cells, which are immortal. CSCs are highly immortal cells that possess multiple mechanisms to prevent cell death. Thus, it is possible that CSCs possess immunogenic antigens that are not expressed in differentiated cancer cells or normal epithelial cells, and that these antigens may be ideal therapeutic targets for cancer treatment. In this study, we obtained CD133+ tumor cells from B16 melanoma cells by repeated isolation with immunomagnetic beads. The purified CD133+ tumor cells possessed CSC properties such as high tumorgenecity in vivo, anchorage independent cell growth and spheroid formation. While the mice vaccinated with CD133- tumor antigens showed no protective immunity, the mice immunized with CD133+ tumor antigens exhibited antitumor immunity against parental melanoma. T cells primed by CD133+ tumor vaccine mediated potent antitumor reactivity, thereby eradicating established parental cancer tissues in vivo. CD133+ tumor antigens tended to prime type 17 helper T (Th17) cells and Th1 cells, but not Th2 cells. Moreover, our proteome analyses revealed that CSCs possess specific proteins. T cells that were primed by the synthesized protein showed specific cytokine release upon CD133+ tumor antigen stimulation. Vaccination with the CSC-specific protein induced protective immunity against parental melanoma. These results indicate that anti-CSC immunotherapy may be a promising strategy to cure cancer, and that CSCs provide unique target proteins. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5165.