Oncolytic measles virus enhances antitumour responses of adoptive CD8(+)NKG2D(+) cells in hepatocellular carcinoma treatment

There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8(+)NKG2D(+) cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8(+)NKG2D(+) cells, mediated by at least three distinct mechanisms. First, MV-Edm infection compelled HCC cells to express the specific NKG2D ligands MICA/B, which may contribute to the activation of CD8(+)NKG2D(+) cells. Second, MV-Edm-infected HCC cells stimulated CD8(+)NKG2D(+) cells to express high level of FasL resulting in enhanced induction of apoptosis. Third, intratumoural administration of MV-Edm enhanced infiltration of intravenously injected CD8(+)NKG2D(+) cells. Moreover, we found that MV-Edm and adoptive CD8(+)NKG2D(+) cells, either administered alone or combined, upregulated the immune suppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in HCC. Elimination of IDO1 by fludarabine enhanced antitumour responses. Taken together, our data provide a novel and clinically relevant strategy for treatment of HCC.