Immunotargeting of the xCT cystine/glutamate antiporter potentiates the efficacy of Her2-targeted immunotherapies in breast cancer

Despite progresses following the introduction of HER2-targeted therapies, HER2+ breast cancer is still characterized by resistance development and metastatic spread in many patients. Cancer stem cells (CSCs) are usually involved in this process, so the combination of HER2- and CSC-targeting could represent a valid approach to treat patients. Our group already identified the cystine-glutamate antiporter xCT as overexpressed in mammary CSCs and demonstrated its fundamental role in their redox balance, self-renewal and resistance to therapies, opening the doors to a new promising targeting opportunity for breast cancer immunotherapy. Anti-HER2 and anti-xCT vaccines were developed using the safe Bovine Herpes Virus (BoHV)-4 vector, which confers immunogenicity to tumor antigens. These vaccines were used alone or in combination to immunize BALB-neuT mice, which are transgenic for rat HER2 and spontaneously develop mammary tumors. Anti-HER2 vaccination significantly impaired primary tumor growth, while anti-xCT vaccination mainly protected from metastasis. The combined vaccination had a complementary effect. We observed both a cytotoxic T cell response and an antibody-dependent cell cytotoxicity due to induction of specific anti-HER2 and anti-xCT antibodies. Moreover, anti-xCT, but not anti-HER2, antibodies impaired CSC viability, self-renewal and migration, resulting in the anti-metastatic action of xCT vaccination. Our results demonstrated that CSC immunotargeting, using anti-xCT vaccination, inhibits metastasis formation independently from HER2 vaccination, and that the two vaccines have a synergic effect. Taken together, these findings provide a new promising strategy for the treatment of HER2+ positive breast cancer.