Vesicular Stomatitis Virus Oncolytic Treatment Interferes with Tumor-Associated Dendritic Cell Functions and Abrogates Tumor Antigen Presentation

Abstract

Oncolytic virotherapy is a promising biological approach to cancer treatment that contributes to tumor eradication via immune-and non-immune-mediated mechanisms. One of the remaining challenges for these experimental therapies is the necessity to develop a durable adaptive immune response against the tumor. Vesicular stomatitis virus (VSV) is a prototypical oncolytic virus (OV) that exemplifies the multiple mechanisms of oncolysis, including direct cell lysis, cellular hypoxia resulting from the shutdown of tumor vasculature, and inflammatory cytokine release. Despite these properties, the generation of sustained antitumor immunity is observed only when VSV is engineered to express a tumor antigen directly. In the present study, we sought to increase the number of tumor-associated dendritic cells (DC) in vivo and tumor antigen presentation by combining VSV treatment with recombinant Fms-like tyrosine kinase 3 ligand (rFlt3L), a growth factor promoting the differentiation and proliferation of DC. The combination of VSV oncolysis and rFLt3L improved animal survival in two different tumor models, i.e., VSV-resistant B16 melanoma and VSV-sensitive E.G7 T lymphoma; however, increased survival was independent of the adaptive CD8 T cell response. Tumorassociated DC were actively infected by VSV in vivo, which reduced their viability and prevented their migration to the draining lymph nodes to prime a tumor-specific CD8 T cell response. These results demonstrate that VSV interferes with tumor DC functions and blocks tumor antigen presentation.Cancer therapy using oncolytic viruses (OV) has achieved remarkable therapeutic effects in numerous preclinical tumor models and clinical trials (4, 30). Of the different OV currently evaluated for efficacy, vesicular stomatitis virus (VSV) has emerged as a prototypical OV based on properties such as cancer cell tropism, cell lysis efficacy, and sensitivity to host antiviral responses (3,24,33). Tumor regression induced by VSV oncolysis is a complex event that is not limited to direct cell killing by virus infection; cellular hypoxia resulting from the shutdown of tumor vasculature also cooperates to reduce tumor burden (7,8). Moreover, the innate immune response and accompanying inflammatory cytokine release contribute to the therapeutic effect observed in various murine models (18,28,36).VSV oncolytic therapy has also been proposed to induce a tumor-specific adaptive immune response because infection and concomitant cell lysis expose tumor antigens within a proinflammatory milieu. Early studies demonstrated the presence of tumor-specific CD8 T cells following VSV treatment and a reduction of the therapeutic effect after CD8 T cell depletion (15). However, subsequent studies indicated that tumor-specific CD8 T cells either were not detected in the tumor, spleen, or draining lymph nodes following VSV treatment (35) or were detected at low levels that were not statistically significant (9,10,17,37). It was also suggested that tumor regression in CD8 T cell depletion experiments was ...

Vesicular Stomatitis Virus Variants Selectively Infect and Kill Human Melanomas but Not Normal Melanocytes

“…In summary, we show that human melanomas are an attractive selective target for VSV-mediated direct oncolysis. The high degree of direct oncolysis in human primary melanoma complements previous work showing that the VSV can initiate or enhance an immune attack on mouse melanoma (26,51,54,55,66).…”

“…Most previous reports on VSV and melanoma focused on mouse melanoma tumors in syngeneic models (25,26,51,52). The most commonly used B16 mouse melanoma model has been referred to in some studies as VSV resistant or partially resistant (24), whereas in others it was shown to be VSV susceptible (53).…”

“…Most of these melanoma studies have focused on mouse melanoma models and have facilitated substantially our current understanding of the role of the immune response in oncolytic virotherapy. However, the most commonly used mouse melanoma cell line B16 may be partially resistant to VSV infection (26). In addition, systemic application of potentially oncolytic virus, which was successfully shown in animal studies on other cancers (22,27) and which is a prerequisite to target a metastatic tumor, remains to be studied with human melanoma.…”

Molecular Pathways: Multimodal Cancer-Killing Mechanisms Employed by Oncolytic Vesiculoviruses

“…For instance, although several reports showed that oncolytic VSV potently activates DCs (22,(24)(25)(26), a recent study by Leveille and colleagues showed that, in contrast, VSV infects and kills DCs and thus impedes antitumor immunity (27). Moreover, while many studies have documented that VSV elicits antitumor immunity, Willmon and colleagues showed that VSV subverts host immunity by engaging a population of myeloid-derived suppressor cells (MDSC; ref.…”

The impact of hypoxia on oncolytic virotherapy

“…99 VSV interferes with tumor dendritic cell function and blocks tumor antigen presentation. 100 Therefore, adjustments need to be made if VSV treatment is combined with other types of immunotherapy regimens. …”