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

Center for Research on Ovarian Cancer Early Detection and Cure, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer biology & therapy (Impact Factor: 3.07). 06/2008; 7(8):1194-205. DOI: 10.4161/cbt.7.8.6216
Source: PubMed


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.

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Available from: Fabian Benencia, Oct 04, 2015
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    • "Interestingly, often these cells do not exert a positive immune influence but act as co-conspirators of tumor growth by inducing regulatory T cell expansion, or directly suppressing T cell responses. These cancer-associated DCs, albeit carrying tumor antigen as we have previously shown (36), express low levels of co-stimulatory molecules (37). Thus, upon encounter with antigen-specific naïve T cells, they can induce an anergic state in these cells favoring tumor immune-escape. "
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    • "These particles were avidly engulfed by TA-DCs, activating them through TLR5 and inducing a potent antitumor immune response. This strategy has the advantage of using the TA-DCs, which might already harbor tumor antigens [194]. If translatable to humans, this will avoid costly ex vivo preparation and pulsing of the patient's DCs. "
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    • "All the primers were designed with the public web Primer 3 program in order to generate PCR products that cross introns and ranging between 85 and 115 bp of length. We have used this program to design the primers described in our previous publications [12,21,23,24]. "
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