Abstract
As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8+ T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials.
Highlights
Despite recent advances in the diagnosis and treatment of breast cancer (BrCa) [1], the burden of this disease remains significant
To determine the oncolytic activity of reovirus (RV) against breast cancer, a panel of human and murine breast cancer cell lines were tested for RV mediated oncolysis
T-47D, SKBR-3, MDA-MB-468, MCF-7, Hs 578T, EMT6 and 4T1 were infected with RV at multiplicity of infection (MOI)
Summary
Despite recent advances in the diagnosis and treatment of breast cancer (BrCa) [1], the burden of this disease remains significant. Cancers 2018, 10, 205 will receive a BrCa diagnosis, accounting for almost 41,000 fatalities in the USA alone [2]. The five-year relative survival of women diagnosed with localized breast cancer is almost 99%, regional and distant-stage disease have five-year survival rates of 84% and 27%, respectively [2]. Novel non-surgical treatment options for these patients are needed. The ability to elicit a potent anti-tumor immune response serves as a logical treatment strategy for this disease. Oncolytic viruses (OV) are a novel group of cancer therapeutics that have the ability to induce such an immune response, and have demonstrated minimal human toxicity to date
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