Despite HER2-targeted therapies improving the outcome of HER2+ breast cancer, many patients experience resistance and metastatic progression. Cancer stem cells (CSC) play a role in this resistance and progression, thus combining HER2 targeting with CSC inhibition could improve the management of HER2+ breast cancer. The cystine-glutamate antiporter, xCT, is overexpressed in mammary CSCs and is crucial for their redox balance, self-renewal, and resistance to therapies, representing a potential target for breast cancer immunotherapy. We developed a combined immunotherapy targeting HER2 and xCT using the Bovine Herpes virus-4 vector, a safe vaccine that can confer immunogenicity to tumor antigens. Mammary cancer- prone BALB-neuT mice, transgenic for rat Her2, were immunized with the single or combined vaccines. Anti-HER2 vaccination slowed primary tumor growth, whereas anti-xCT vaccination primarily prevented metastasis formation. The combination of the two vaccines exerted a complementary effect by mediating the induction of cytotoxic T cells and of HER2 and xCT antibodies that induce antibody-dependent cell-mediated cytotoxicity and hinder cancer cell proliferation. Antibodies targeting xCT, but not those targeting HER2, directly affected CSC viability, self-renewal, and migration, inducing the antimetastatic effect of xCT vaccination. Our findings present a new therapy for HER2+ breast cancer, demonstrating that CSC immunotargeting via anti-xCT vaccination synergizes with HER2-directed immunotherapy.

Immunotargeting of the xCT cystine/glutamate antiporter potentiates the efficacy of HER2-targeted immunotherapies in breast cancer / Conti, L.; Bolli, E.; Di Lorenzo, A.; Franceschi, V.; Macchi, F.; Riccardo, F.; Ruiu, R.; Russo, L.; Quaglino, E.; Donofrio, G.; Cavallo, F.. - In: CANCER IMMUNOLOGY RESEARCH. - ISSN 2326-6066. - 8:8(2020), pp. 1039-1053. [10.1158/2326-6066.CIR-20-0082]

Immunotargeting of the xCT cystine/glutamate antiporter potentiates the efficacy of HER2-targeted immunotherapies in breast cancer

Franceschi V.;MacChi F.;Donofrio G.
;
2020-01-01

Abstract

Despite HER2-targeted therapies improving the outcome of HER2+ breast cancer, many patients experience resistance and metastatic progression. Cancer stem cells (CSC) play a role in this resistance and progression, thus combining HER2 targeting with CSC inhibition could improve the management of HER2+ breast cancer. The cystine-glutamate antiporter, xCT, is overexpressed in mammary CSCs and is crucial for their redox balance, self-renewal, and resistance to therapies, representing a potential target for breast cancer immunotherapy. We developed a combined immunotherapy targeting HER2 and xCT using the Bovine Herpes virus-4 vector, a safe vaccine that can confer immunogenicity to tumor antigens. Mammary cancer- prone BALB-neuT mice, transgenic for rat Her2, were immunized with the single or combined vaccines. Anti-HER2 vaccination slowed primary tumor growth, whereas anti-xCT vaccination primarily prevented metastasis formation. The combination of the two vaccines exerted a complementary effect by mediating the induction of cytotoxic T cells and of HER2 and xCT antibodies that induce antibody-dependent cell-mediated cytotoxicity and hinder cancer cell proliferation. Antibodies targeting xCT, but not those targeting HER2, directly affected CSC viability, self-renewal, and migration, inducing the antimetastatic effect of xCT vaccination. Our findings present a new therapy for HER2+ breast cancer, demonstrating that CSC immunotargeting via anti-xCT vaccination synergizes with HER2-directed immunotherapy.
2020
Immunotargeting of the xCT cystine/glutamate antiporter potentiates the efficacy of HER2-targeted immunotherapies in breast cancer / Conti, L.; Bolli, E.; Di Lorenzo, A.; Franceschi, V.; Macchi, F.; Riccardo, F.; Ruiu, R.; Russo, L.; Quaglino, E.; Donofrio, G.; Cavallo, F.. - In: CANCER IMMUNOLOGY RESEARCH. - ISSN 2326-6066. - 8:8(2020), pp. 1039-1053. [10.1158/2326-6066.CIR-20-0082]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2999513
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