Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types,only a small subset of patients can benefit from PD-1/PD-L1 blockade.CD47 expressed on tumor cells...Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types,only a small subset of patients can benefit from PD-1/PD-L1 blockade.CD47 expressed on tumor cells protects them from phagocytosis through interaction with SIRPαon macrophages,while PD-L1 dampens T cell-mediated tumor killing.Therefore,dual targeting PD-L1 and CD47 may improve the efficacy of cancer immunotherapy.A chimeric peptide Pal-DMPOP was designed by conjugating the double mutation of CD47/SIRPαblocking peptide(DMP)with the truncation of PD-1/PD-L1 blocking peptide OPBP-1(8-12)and was modified by a palmitic acid tail.Pal-DMPOP can significantly enhance macrophage-mediated phagocytosis of tumor cells and activate primary T cells to secret IFN-γin vitro.Due to its superior hydrolysis-resistant activity as well as tumor tissue and lymph node targeting properties,Pal-DMPOP elicited stronger anti-tumor potency than Pal-DMP or OPBP-1(8-12)in immune-competent MC38 tumor-bearing mice.The in vivo anti-tumor activity was further validated in the colorectal CT26 tumor model.Furthermore,Pal-DMPOP mobilized macrophage and T-cell anti-tumor responses with minimal toxicity.Overall,the first bispecific CD47/SIRPαand PD-1/PD-L1 dual-blockade chimeric peptide was designed and exhibited synergistic anti-tumor efficacy via CD8^(+)T cell activation and macrophage-mediated immune response.The strategy could pave the way for designing effective therapeutic agents for cancer immunotherapy.展开更多
基金the National Natural Science Foundation of China(U20A20369,81901687)Shenzhen Science and Technology Program(KQTD20190929173853397)+1 种基金“Pearl River Talent Plan”Innovation and Entrepreneurship Team Project of Guangdong Province(2019ZT08Y464)Science,Technology and Innovation Commission of Shenzhen Municipality(JCYJ20190807154819245)。
文摘Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types,only a small subset of patients can benefit from PD-1/PD-L1 blockade.CD47 expressed on tumor cells protects them from phagocytosis through interaction with SIRPαon macrophages,while PD-L1 dampens T cell-mediated tumor killing.Therefore,dual targeting PD-L1 and CD47 may improve the efficacy of cancer immunotherapy.A chimeric peptide Pal-DMPOP was designed by conjugating the double mutation of CD47/SIRPαblocking peptide(DMP)with the truncation of PD-1/PD-L1 blocking peptide OPBP-1(8-12)and was modified by a palmitic acid tail.Pal-DMPOP can significantly enhance macrophage-mediated phagocytosis of tumor cells and activate primary T cells to secret IFN-γin vitro.Due to its superior hydrolysis-resistant activity as well as tumor tissue and lymph node targeting properties,Pal-DMPOP elicited stronger anti-tumor potency than Pal-DMP or OPBP-1(8-12)in immune-competent MC38 tumor-bearing mice.The in vivo anti-tumor activity was further validated in the colorectal CT26 tumor model.Furthermore,Pal-DMPOP mobilized macrophage and T-cell anti-tumor responses with minimal toxicity.Overall,the first bispecific CD47/SIRPαand PD-1/PD-L1 dual-blockade chimeric peptide was designed and exhibited synergistic anti-tumor efficacy via CD8^(+)T cell activation and macrophage-mediated immune response.The strategy could pave the way for designing effective therapeutic agents for cancer immunotherapy.
