Abstract 3553: xCT is a new cancer stem cell immunotherapeutic target for breast cancer

The several unsuccessful treatments in metastatic cancers might miss cancer stem cells (CSC), a sub-population of cells with a critical role in cancer. By contrast, a vaccine-elicited immune response against CSC might be particularly effective. The identification of oncoantigens (OA) expressed by CSC may provide new targets for effective anticancer vaccines. To this purpose, the transcription profile of the ErbB2 + TUBO mammary cancer cell line was compared with that of TUBO cells grown under specific conditions to generate CSC-enriched mammospheres. Integrating the data obtained with meta-analyses of seven independent human breast tumor data sets we identified new CSC mammary OA that were validated both in vitro and in vivo. Among the identified OA, we focused on xCT, a channel that supports glutathione synthesis regulating the intracellular redox balance. We observed that xCT expression increases in TUBO and 4T1 derived mammospheres; its silencing, obtained with specific siRNA, or incubating mammospheres with its inhibitor sulfasalazine (2), significantly reduces TUBO cells ability to generate mammospheres. In vivo xCT inhibition impaired CSC ability to generate lung metastases derived both from an intravenous injection of TUBO-derived mammospheres and from subcutaneous 4T1 tumors; furthermore, this effect was improved when combined with the cytotoxic drug doxorubicin. Moreover, the anti xCT vaccination of mice bearing mammosphere-derived tumors both from TUBO and 4T1 cells reduced the speed of tumor growth. In conclusion, this study provides a genomic characterization of mammary CSC and identifies fresh target for new and potentially effective anticancer vaccines, thus providing a new tool for the design of combined therapeutic approaches that efficaciously target both CSC and more differentiated cells in breast cancers, leading to both cancer treatment and prevention of metastases and recurrence. BIBLIOGRAPHY 1. Nagano O et al., Oncogene 2013. 2. Chen RS et al., Oncogene 2009. Citation Format: Marco Macagno, Stefania Lanzardo, Laura Conti, Roberto Ruiu, Raffaele A. Calogero, Federica Cavallo. xCT is a new cancer stem cell immunotherapeutic target for breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3553. doi:10.1158/1538-7445.AM2015-3553