Recombinant Vesicular Stomatitis Virus Transduction of Dendritic Cells Enhances Their Ability to Prime Innate and Adaptive Antitumor Immunity
Title:Recombinant Vesicular Stomatitis Virus Transduction of Dendritic Cells Enhances Their Ability to Prime Innate and Adaptive Antitumor Immunity
Publication:Published in: Molecular Therapy
Volume: 17, Issue: 8, Pages: 1465-1472
In this paper, Boudreau et al. examined the effectiveness of using a mutant vesicular stomatitis virus (VSV) as a transduction and maturation vector for dendritic cells (DC) as an ex vivo vaccine of sorts. Briefly, cells from the bone marrow of C57BL/6 mice were collected and cultured in the presence of GM-CSF for 7 days to induce differentiation into DC. The authors infected the cells with VSV containing a deletion of methionine from the 51st amino acid position in the Matrix protein. Several previous studies have demonstrated that the introduction of this mutation almost completely prevents the virus from inhibiting the host cell type I interferon induction, and has a potent attenuating effect on virus replication. This is precisely what the authors observed. Interestingly, high levels of transgene expression was still observed in dendritic cells, while only having a minimal effect on DC viability. This is interesting in that wild type VSV rapidly induces death of infected cells. The high post-infection viability observed is likely a result of the capability of DCs to produce large amounts of IFN.
However, expression of transgene is not enough for DC to be able to induce an immune response. Activation of the cells, which results in high expression of antigen presenting molecules (MHC-II) as well as CD40 and CD80/86, which are critical “danger signal” receptors for the activation of immune effector cells, such as NK or CD8+ T cells. Infection with mutant VSV exhibited potent activation of DC in vitro.
When the transduced and activated DC were re-introduced to mice challenged with B16-OVA cells which induce numerous tumors in lung tissue, there was a pronounced decrease in the number of tumors in mice reconstituted with the VSV-SIIN tumor antigen primed DC. Further investigation demonstrated a significant increase in the expression of INF-gamma producing and CD69+ NK cells as well as IFN-gamma CTLs, and exhibited antigen specific killing of target cells. To confirm the role of both CTL and NK cells, mice were gradually depleted of these cells by repeated administration of cell targeting antibodies. This resulted in a dramatic increase in the number of tumors in DC vaccinated mice.
There were several aspects of this article that I liked. First was the demonstration of the VSV mutant vector was able to produce large amounts of antigen within DC, while minimal production of infectious virus was produced. This speaks volumes to the safety of the therapeutic potential of VSV. Second, the simple design of the experiments clearly demonstrated the desired effect and a mechanism of action. Finally, I appreciate the authors’ acknowledgement of the shortcomings of this study; that VSV or VSV activation of DC alone are not likely to be sufficient as a “cure for cancer.” However, it does show strong promise in the form of a combination therapeutic. One glaring issue that struck me while reading this paper was that the mutant VSV alone had nearly as strong of an effect on the activation of DC, Nk and CTL as did the vaccine. They demonstrated that not only were the CTL and NK cells specifically targeting SIIN expressing cells, but also cells expressing peptides from the VSV nucleocapsid protein. This could profoundly limit the efficacy of this approach as is. Although the location of the SIIN peptides was not explicitly stated, the 5th gene position within the VSV genome is where they are commonly placed. As the authors mentioned, the N gene is expressed upstream of the antigen, and cited this as a possible reason for the background cytotoxic effector cell functions. It would be interesting to see how moving the antigenic peptides proximally within the genome would increase the potency and specificity of the responses.