Blocking feedback immunosuppression of antigen presentation in brain tumor during oncolytic virotherapy with oHSV-mshPKR.

Abstract

Glioblastoma (GBM) is the most frequent malignant brain tumor. We recently discovered that oncolytic herpes simplex virus engineered to disable tumor-intrinsic protein kinase R (PKR) signaling (oHSV-shPKR) could increase oHSV oncolysis and anti-tumor immune response. However, here we show that disabling tumor-intrinsic PKR signaling can also induce the activation of the indoleamine 2,3-dioxygenase (IDO) signaling pathway. Both GBM tumor progression and oHSV intratumoral therapy increased infiltration of IDO+CD11c+ dendritic cells into the tumor. The coculture of oHSV-infected human GBM neurospheres with monocytes-derived dendritic cells (MoDCs) dramatically increased IDO signaling activation in MoDCs through type-I interferon signaling. Addition of IDO inhibitor (indoximod) in the coculture significantly increased MoDCs activation and reduced the consumption of tryptophan. Combining indoximod and oHSV significantly inhibited tumor growth, and induced antigen specific CD8+ T cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of glioblastoma.