| Hepatocellular carcinoma(HCC)is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths.Cancer immunotherapy holds the promise to cure maliganancies.Oncolytic virus-immunotherapy(immune-virotherapy)is an emerging strategy that can effectively initiate antitumor immune responses.Due to its excellent safety records and easy to be modified,attenuated measles virus vaccine Edmonston strain(MV-Edm)has been investigated in several clinical trials to treat advanced cancer patients.However,little is know about MV-Edm in antitumor immunotherapy.In this sudy,we exploited a model of adoptive transplantation of CD8+NKG2D+cells,and systemically investigated the potency of MV-Edm for antitumor immunotherapy in HCC.We demonstrated that MV-Edm infection induced immunogenic cell death(ICD)in HCC cell lines-LM3 and 97H,including calreticulin surface exposure,release of HMGB1 and ATP.We showed that in vitro MV-Edm infection in HCC further enhanced CD8+NKG2D+ cells mediated oncolysis.Moreover,we found that MV-Edm upregulated the expression of MICA/B on hepatocellular carcinoma cells,which possibly enhance the activation of CD8+NKG2D+cells via interacting with NKG2D molecule.Interestingly,MV-Edm infection in HCC cells upregulated FasL expression on CD8+NKG2D+ cells,which further enhanced oncolytsis via recognizing its cognate receptor Fas expressed on cancer cells.In a subcutaneous HCC mouse model,intratumoral administration of MV-Edm significantly enhanced the infiltration of CD8+NKG2D+ cells into tumor mass,and also massively increased activation of CD8+NKG2D+ cells resulted in a profound inhibition of tumor growth and prolonged survival time of mice.Indoleamine 2,3-dioxygenase(IDO1)is an immunosuppressive enzyme that catalyzes tryptophan into kynurenine,and in turn inhibited antitumor immune responses.IDO1 is known to be produced by tumor cells and by some immune cells.We found that MV-Edm and CD8+NKG2D+cells massively upregulated IDO1 both in vitro and in vivo,when IDO1 was decreased by fludarabine,the antitumor activity of CD8+NKG2D+ cells was then further significantly improved,which results in a more profound inhibition of tumor growth and prolonged survival of mice.In conclusion,our study provides evidences that MV-Edm can be well used not only for direct oncolysis but also for improving antitumor immunotherapy in HCC.When combined with adoptive transplantation of CD8+NKG2D+ cells,MV-Edm can not only directly enhance their oncolysis,but also can effectively recruit them to tumor sites and activate them in situ.Furthermore,inhibition of IDO1 by a chemotherapeutic agent fludarabine can further enhance the antitumor immunity.Given that MV-Edm and adoptive T cell therapy have been both investigated in clinic for advanced cancer patients,our data provides a novel strategy that combines MV-Edm with CD8+NKG2D+ cells and fludarabine for HCC treatment,which can be translated into clinical application in the future. |
