Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years,but the limited efficiency of their infiltration into solid tumors makes it difficult to ...Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years,but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone.In this study,an oncolytic virus(rVSV-LCMVG)that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells.By transforming the immunosuppressive tumor microenvironment into an immunosensitive one,in B16 tumor-bearing mice,combination therapy showed superior antitumor effects than monotherapy.This occurred whether the OV was administered intratumorally or intravenously.Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8^(+)T cells to the TME to trigger antitumor immune responses.Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment,downregulating the expression of PD-1,and restoring effector T-cell function.To offer a combination therapy with greater translational value,mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells.The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival.This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens,in terms of synergistic efficacy and mechanism.展开更多
基金supported by National Natural Science Foundation of China grants 82322027(to T.Z.),82341043(to T.Z.),32170943(to T.Z.),81991491(to N.X.),32300744(to H.X.)Fundamental Research Funds for the Central Universities 20720220003(to N.X.)。
文摘Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years,but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone.In this study,an oncolytic virus(rVSV-LCMVG)that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells.By transforming the immunosuppressive tumor microenvironment into an immunosensitive one,in B16 tumor-bearing mice,combination therapy showed superior antitumor effects than monotherapy.This occurred whether the OV was administered intratumorally or intravenously.Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8^(+)T cells to the TME to trigger antitumor immune responses.Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment,downregulating the expression of PD-1,and restoring effector T-cell function.To offer a combination therapy with greater translational value,mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells.The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival.This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens,in terms of synergistic efficacy and mechanism.
