Oncolytic measles virus induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by human myeloid and plasmacytoid dendritic cells

Abstract

ABSTRACTAttenuated measles virus (MV) is currently being evaluated in clinical trials as an oncolytic therapeutic agent. Originally used for its lytic activity against tumor cells, it is now admitted that the effectiveness of MV also lies in its ability to initiate antitumor immune responses through the activation of dendritic cells (DCs). In this study, we investigated the capacity of oncolytic MV to convert human blood myeloid CD1c+ DCs and plasmacytoid DCs (pDCs) into cytotoxic effectors. We found that MV induces the expression of the cytotoxic protein TNF-related apoptosis-inducing ligand (TRAIL) on the surface of DCs. We demonstrate that the secretion of interferon-α (IFN-α) by DCs in response to MV is responsible for this TRAIL expression. Several types of PRRs (pattern recognition receptors) have been implicated in MV genome recognition, including RLRs (RIG-I-like receptors) and TLRs (Toll-like receptors). We showed that CD1c+ DCs secrete modest amounts of IFN-α and express TRAIL in an RLR-dependent manner upon exposure to MV. In pDCs, MV is recognized by RLRs and also by TLR7, leading to the secretion of high amounts of IFN-α and TRAIL expression. Finally, we showed that MV-stimulated DCs induce TRAIL-mediated cell death of Jurkat cells, confirming their acquisition of cytotoxic functions. Our results demonstrate that MV can activate cytotoxic myeloid CD1c+ DCs and pDCs, which may participate to the antitumor immune response.