Abstract
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.
Highlights
Novel effective approaches are urgently required for treatment of hepatocellular carcinoma (HCC)
We confirmed that CD8+NKG2D+ cells exerted well oncolysis when mixed with HCC cells at a ratio (E:T) over 5 to 1 (Fig. 1b)
We found that measles virus vaccine strain Edmonston (MV-Edm)-infected HCC cells were more sensitive to CD8+NKG2D+mediated oncolysis (Fig. 1c)
Summary
Novel effective approaches are urgently required for treatment of hepatocellular carcinoma (HCC). To achieve optimal antitumour immunity, OVs have been genetically modified to express tumour associated antigens (such as NY-ESO-1 or PSA) to prime and boost specific antitumour immune responses[4,5,6], or to express cytokines (e.g. GM-CSF, IL-15) to augment activation of immune cells[7,8,9]. Adoptive cell transfer immunotherapy is an emerging approach to cancer treatment includes adoptive T cells, CAR T cells and cytokine induced killer (CIK) cells[20, 21]. Induced IDO1 may counter-regulate antitumour immune responses by means of immunotherapy including viro-immunotherapy. It is yet unknown whether IDO1 play a role in OV-mediated antitumour immunity
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