Immunotargeting of the xCT Cystine/Glutamate Antiporter Potentiates the Efficacy of HER2-Targeted Immunotherapies in Breast Cancer.

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.

journal_name

Cancer Immunol Res

authors

Conti L,Bolli E,Di Lorenzo A,Franceschi V,Macchi F,Riccardo F,Ruiu R,Russo L,Quaglino E,Donofrio G,Cavallo F

doi

10.1158/2326-6066.CIR-20-0082

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

1039-1053

issue

8

eissn

2326-6066

issn

2326-6074

pii

2326-6066.CIR-20-0082

journal_volume

8

pub_type

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