Bovine herpesvirus 4-based vector delivering the full length xCT DNA efficiently protects mice from mammary cancer metastases by targeting cancer stem cells

Abstract

Despite marked advancements in its treatment, breast cancer is still the second leading cause of cancer death in women, due to relapses and distal metastases. Breast cancer stem cells (CSCs), are a cellular reservoir for recurrence, metastatic evolution and disease progression, making the development of novel therapeutics that target CSCs, and thereby inhibit metastases, an urgent need. We have previously demonstrated that the cystine-glutamate antiporter xCT (SLC7A11), a protein that was shown to be overexpressed in mammary CSCs and that plays a key role in the maintenance of their redox balance, self-renewal and resistance to chemotherapy, is a potential target for mammary cancer immunotherapy. This paper reports on the development of an anti-xCT viral vaccine that is based on the bovine herpesvirus 4 (BoHV-4) vector, which we have previously showed to be a safe vaccine that can transduce cells in vivo and confer immunogenicity to tumor antigens. We show that the vaccination of BALB/c mice with BoHV-4 expressing xCT (BoHV-4-mxCT), impaired lung metastases induced by syngeneic mammary CSCs both in preventive and therapeutic settings. Vaccination induced T lymphocyte activation and the production of anti-xCT antibodies that can mediate antibody-dependent cell cytotoxicity (ADCC), and directly impair CSC phenotype, self-renewal and redox balance. Our findings pave the way for the potential future use of BoHV-4-based vector targeting xCT in metastatic breast cancer treatment.

Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

“…In a similar way, a newer VLP vaccine that displays the third extracellular domain of xCT (ECD3), whose sequence is longer than that of ECD6, resulting in a major oligoclonal antibody response, can neutralize xCT function and impair breast cancer cell proliferation and metastasization [ 61 ]. Finally, the bovine herpesvirus 4 (BoHV-4)-based anti-xCT vaccine, which exploits a safe viral vector that confers immunogenicity to tumor antigens, has proven to be effective in impairing lung metastasis and inducing T lymphocyte activation, anti-xCT antibody production and ADCC in mouse mammary cancer models [ 53 ]. It is worth noting that anti-xCT vaccination impairs metastasis formation in a spontaneous mouse model of HER2 + mammary cancer, and synergizes with HER2-targeted therapies [ 56 ].…”

Targeting ferroptosis in breast cancer

“…In 2018, Bolli et al showed that inhibition of xCT by virus-like-particle immunotherapy could reduce the metastatic potential of breast cancer stem cells [316]. Vaccines targeting SLC7A11 have been developed and demonstrated to protect mice from mammary cancer metastases [317,318].…”

Bovine Herpesvirus-4-Vectored Delivery of Nipah Virus Glycoproteins Enhances T Cell Immunogenicity in Pigs

“…The BoHV-4 TK genomic region is strongly conserved among BoHV-4 isolates [15], therefore ensuring the stability of the genomic locus from potential recombination when foreign DNA sequences are inserted. Previous studies have shown that interrupting the TK locus by the insertion of foreign DNA sequences [53] of different sizes does not interfere with viral replication in vitro and heterologous protein expression is maintained [36,37,39,[41][42][43][44]54,55]. However, the inactivation of herpesvirus TK gene results in severe attenuation in vivo [54,56,57]; reducing the risks associated to the use of herpesviral vectors [58,59].…”

“…Lastly, BoHV-4 can be manipulated using infectious BoHV-4-derived bacterial artificial chromosome (BAC) genomes cloned in Escherichia coli as a tool to readily modify the viral genome [36]. Recombinant BoHV-4 vectors expressing heterologous antigens have been shown to be immunogenic and efficacious in mice [37][38][39][40][41], sheep [42], rabbits [43], goats [44], and pigs [45].…”