We have previously shown that intratumor administration of HSV-1716 (an ICP34.5 null mutant) resulted in significant reduction of
tumor growth and a significant survival advantage in a murine model of
ovarian cancer. Herewith we report that oncolytic HSV-1716 generates vaccination effects in the same model. Upon HSV-1716
infection, mouse ovarian
tumor cells showed high levels of expression viral
glycoproteins B and D and were highly phagocyted by dendritic cells (DCs). Interestingly, increased phagocytosis of
tumor-infected cells by DCs was impaired by
heparin, and anti-HSV
glycoproteins B and D, indicating that
viral infection enhances adhesive interactions between DCs and
tumor apoptotic bodies. Moreover, HSV-1716 infected cells expressed high levels of
heat shock proteins 70 and
GRP94, molecules that have been reported to induce maturation of DCs, increase cross-presentation of
antigens and promote antitumor immune response. After phagocytosis of
tumor-infected cells, DCs acquired a mature status in vitro and in vivo, upregulated the expression of costimulatory molecule and increased migration towards
MIP-3beta. Furthermore, HSV-1716 oncolytic treatment markedly reduced
vascular endothelial growth factor (
VEGF) levels in
tumor-bearing animals thus abrogating
tumor immunosuppressive milieu. These mechanisms may account for the highly enhanced antitumoral immune responses observed in HSV-1716 treated animals. Oncolytic treatment induced a significantly higher frequency of
tumor-reactive IFNgamma producing cells, and induced a robust
tumor infiltration by T cells. These results indicate that oncolytic
therapy with HSV-1716 facilitates antitumor immune responses.