4613347712

Levels of gp33-specific T celi responses do not correlate with prolonged mice survival.

We then sought to determine if the ability of VSV mutants to induce a gp33-specific T celi responses correlated with an improved therapeutic efficacy. Surprisingly, although the Gór mutant was the most potent in terms of polyfimctional antitumor CD8⁺ T celi induction, it did not slow down tumor progression significantly morę than other VSV mutants nor WT VSV (Fig. 4). Oppositely, treatment with the M mutant, although it was the poorest at inducing gp33-specific T celi responses, prolonged mice survival to a similar degree as the WT or G mutants. Altogether, these results demonstrate that the capacity to induce a stronger immune response against the gp33 surrogate tumor epitope does not necessarily correlate with improved therapeutic efficacy.

VSV oncolytic therapy efficacy is CD8*T celi dependent.

Since Mmsir treatment led to prolonged mice survival despite a reduced CTL response against the surrogate tumor antigen gp33, we assessed whether tumor-specific CD8⁺ T lymphocytes were important for tumor control. To do so, we adoptively-transferred purified CD8⁺ T cells, harvested 4 days after the last VSV treatment of B16gp33 melanoma-bearing mice, into naive mice. We then inoculated recipient mice with the parental B16 tumor celi linę and followed tumor progression. We found that tumor-specific CD8⁺ T lymphocytes generated following treatment with VSV mutants are a major factor in tumor control and can slow down tumor growth efficiently (Fig. 5a). However, tumor-specific CD8⁴ T cells generated by treatment with WT VSV did not significantly slow-down B16 tumor progression even if a strong and functional gp33-specific immune response was induced. On the other hand, CD8⁺ T cells harvested from MMsiR-treated mice efficiently controlled tumor burden despite the fact that this virus induced a poor gp33-specific T celi response. Transfer of CD8⁺ T cells from VSV Gó-, Gór- and MMsiR-treated B16gp33-bearing mice correlated with better survival rates (Fig. 5b). These results show that the strength of the immune response induced against a surrogate tumor antigen does not adequately predict tumor control in vivo and suggest that the Mmsir mutant may be able to induce a protective CTL response against a broader pool of endogenous tumor antigens using different mechanisms when compared to the WT virus or G mutants.