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.
Highlights
Breast cancer is, together with colon and lung cancers, one of the three most frequent cancers worldwide, and the most common in women
Results xCT expression is linked to poor prognosis in Her2+ breast cancer patients
To analyze if the same was true for Her2+ breast cancer, we ran a meta-analysis on a set of publicly available microarray data from breast cancer patients (27)
Summary
Together with colon and lung cancers, one of the three most frequent cancers worldwide, and the most common in women. Its prognosis has improved, thanks to the progresses achieved in its early detection and therapy. It still represents the second cause of cancer deaths in developed countries, and its incidence and mortality are progressively increasing in Asia, Africa and South America (1). Most patients affected by metastatic disease display primary or secondary resistance to Her2-targeted therapies. This eventually leads to disease progression despite treatment, and advanced Her2+ breast cancer remains almost incurable (3). The development of new therapeutic approaches able to increase the efficacy of Her2-targeting drugs is urgently needed
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