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

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.

<p>DEP Domain-Containing Protein 1B (DEPDC1B) Promotes Migration and Invasion in Pancreatic Cancer Through the Rac1/PAK1-LIMK1-Cofilin1 Signaling Pathway</p>

“…RNA was extracted, purified and converted to cDNA using an oPlus kit and PrimeScript RT Master Mix (Takara Bio Inc., Naha, Japan) according to the manufacturer's protocol. 16 Quantitative real-time PCR was performed using a ViiA 7 real-time PCR system (Applied Biosystems, Thermo Fisher Scientific, Rockford, IL, USA) and SYBR Green PCR master mix. The primers used for real-time PCR were as follows: DEPDC1B forward 5′-AGCTACCAGGCTGTGGAATG-3′ and reverse 5′-AGCTCTTGAAACGACAGCGA-3′; GAP DH forward 5′-CCATGTTCGTCATGGGTGTGAACCA-3′ and reverse 5′-GCCAGTAGAGGCAGGGATGATGTTC-3′.…”

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

“…Oncolytic viruses (OVs) have double functions of direct cytotoxicity and induction of effective anti-tumor immune responses [82]. The research reports from Chen et al [83] showed that the intratumoral injection of measles virus vaccine strain Edmonston (MV-EDM) could induce the expression of specific ligand MICA and MICB on the surface of hepatoma cells, and thereby could significantly enhance the cytotoxicity of CD8 + NKG2D + T cells to hepatocellular carcinoma. It could also enhance the expression of FasL in CD8 + NKG2D + cells, but had no effect on the expression of Fas in hepatoma cells.…”

Heating it up: Oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies

“…Therapeutic administration of oncolytic viruses (OV) into tumors promotes strong antiviral immune response accompanied by the production of cytokines such as type-1 interferons and chemokines. 17 , 26-28 Type-1 interferons promote the expression of PD-L1 on the surface of cancer cells, while chemokines like CCL3 and CCL4 attract immune cells which often express PD-1 or CTLA-4. 29-32 Thus, antiviral immunological events inflame the tumor and make it ‘hot’.…”