Article: article from journal or magazin.
Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation.
Cancer Biology and Therapy
Publication types: Journal Article ; Research Support, N.I.H., ExtramuralPublication Status: ppublish
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.
Animals, Antigen Presentation/genetics, Antigen Presentation/immunology, Antigens, Neoplasm/genetics, Antigens, Neoplasm/immunology, Female, Immunohistochemistry, Mice, Mice, Inbred C57BL, Neoplasms/immunology, Neoplasms/therapy, Oncolytic Virotherapy/methods, Ovarian Neoplasms/immunology, Ovarian Neoplasms/therapy, Simplexvirus/genetics, Simplexvirus/immunology, Tumor Cells, Cultured
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