Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation.

Abstract

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.

• Authors: Fabian Benencia, Maria C Courrèges, Nigel W Fraser, George Coukos
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 7 Issue 8 Pg. 1194-205 (Aug 2008) ISSN: 1555-8576 [Electronic] United States
• PMID: 18458533 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Neoplasm

Topics

• Animals
• Antigen Presentation (genetics, immunology)
• Antigens, Neoplasm (genetics, immunology)
• Female
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Neoplasms (immunology, therapy, virology)
• Oncolytic Virotherapy (methods)
• Ovarian Neoplasms (immunology, therapy, virology)
• Simplexvirus (genetics, immunology)
• Tumor Cells, Cultured