Programmed death ligand 1(PD-L1)immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is<20%.Some chemotherapeutic drugs could also activate an anticancer immune r...Programmed death ligand 1(PD-L1)immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is<20%.Some chemotherapeutic drugs could also activate an anticancer immune response to kill cancer cells,apart from their direct cytotoxicity.Our study investigated the combination of chemotherapeutic drugs with PD-L1 antibody to enhance the response rate of PD-L1 blockade.Non-small cell lung cancer(NSCLC)cells were pre-treated with mitomycin C(MMC)and then co-cultured with peripheral blood mononuclear cells(PBMCs)to investigate the effect of the combination of MMC with PD-L1 antibody.The drug combination was also evaluated in vivo in Lewis lung cancer(LLC)cells-bearing C57BL/6 mice.MMC increased the expressions of PD-L1 and MHC-I in NSCLC cells in vitro and in vivo and enhanced the cytotoxic effect of lymphocytes on NSCLC in vitro.In LLC-bearing mouse model,the combination of MMC and PD-L1 antibody was found to be more effective in retarding tumor growth and prolonging overall survival than either single treatment alone,which was associated with increased lymphocyte infiltration and granzyme B release.Mechanistically,MMC activated the ERK pathway,which subsequently enhanced the binding of c-JUN to the PD-L1 promoter and recruited its co-factor STAT3 to increase PD-L1 expression.The upregulated ERK pathway was shown to activate p65 to increase the MHC-I expression.MMC was shown to enhance the efficacy of PD-L1 blockade in NSCLC cells.Further study is warranted to translate the findings to clinical application.展开更多
基金supported by grants from the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(No:2018ZX09711002)the National Natural Science Foundation of China(No:81673463)+1 种基金the National Natural Science Foundation of China(No:81703545)Guangdong Esophageal Cancer Institute Science and Technology Program(No:M201705).
文摘Programmed death ligand 1(PD-L1)immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is<20%.Some chemotherapeutic drugs could also activate an anticancer immune response to kill cancer cells,apart from their direct cytotoxicity.Our study investigated the combination of chemotherapeutic drugs with PD-L1 antibody to enhance the response rate of PD-L1 blockade.Non-small cell lung cancer(NSCLC)cells were pre-treated with mitomycin C(MMC)and then co-cultured with peripheral blood mononuclear cells(PBMCs)to investigate the effect of the combination of MMC with PD-L1 antibody.The drug combination was also evaluated in vivo in Lewis lung cancer(LLC)cells-bearing C57BL/6 mice.MMC increased the expressions of PD-L1 and MHC-I in NSCLC cells in vitro and in vivo and enhanced the cytotoxic effect of lymphocytes on NSCLC in vitro.In LLC-bearing mouse model,the combination of MMC and PD-L1 antibody was found to be more effective in retarding tumor growth and prolonging overall survival than either single treatment alone,which was associated with increased lymphocyte infiltration and granzyme B release.Mechanistically,MMC activated the ERK pathway,which subsequently enhanced the binding of c-JUN to the PD-L1 promoter and recruited its co-factor STAT3 to increase PD-L1 expression.The upregulated ERK pathway was shown to activate p65 to increase the MHC-I expression.MMC was shown to enhance the efficacy of PD-L1 blockade in NSCLC cells.Further study is warranted to translate the findings to clinical application.
