4613347715

Oncolytic virotherapy nas proven to be a promising cancer treatment in several successfui clinical studies (Gaianis et al., 2010; Heo et al., 2013a; Reid et al., 2002). VSV, one of the most studied prototypie oncolytic viruses, is now in clinical trials for liver cancer treatment in the United States (NCTO1628640). However, a number of ąuestions remain unanswered about the mechanisms that contribute to virotherapy efflcacy. One such ąuestion is the relative contribution of the immune response versus the intrinsic oncolytic activity of a particular virus to the treatment outeome. To address this ąuestion and assess if a virus mutational status impacts the antitumoral immune response, we sought to determine the ability of WT, M and G VSV mutants to induce tumor-specific immune responses and contro 1 tumor progression.

We found that the in vitro replication potential of the various VSV strains studied did not correlate with their respective capacity to persist in tumor tissue in vivo. Since point mutations in the Gó and Gór mutants are proximal to the dominant neutralizing VSV epitope (Vandepol et al., 1986), we tested whether the development of the neutralizing antibody response agamst the G mutants was affected compared to the M mutant or WT VSV G mutants induced a similar neutralizing antibody response with an efficient class switch to IgGs, contributing to their fast and effective clearance. Point mutations could have also modified the cross-neutralization ability of the antibodies induced. However, mutations in Gó and Gór did not impair neutralization of the WT viral particie, lnterestingly, we observed a reduced neutralizing antibody response after Mmsir virus infection. This decreased B celi response along with the diminished CTL response observed against VSV Mmsir may in fact allow for the establishment of a broader antitumoral response. While the WT, Gó and Gór mutants induce a stronger antiviral response, this response may limit the ability of VSV to induce a T celi response to tumor antigens.

Wild-type VSV was the most potent at promoting tumor infiltration by immune cells. Characterization of immune subpopulations within the tumor microenvironment showed a large proportion of T and B cells, as well as MDSC. VSV treatment also led to a decreased

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