Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients.Here,we discovered that the novel immune checkpoint VISTA is highl...Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients.Here,we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells,especially myeloid derived suppressor cells(MDSCs)and CD8^(+)T cells.Then,peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique,and its mutant peptide VS3 was obtained by molecular docking based mutation.Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition,and elicit anti-tumor activity in vivo.The peptide DVS3-Pal was further designed by D-amino acid substitution and fatty acid modification,which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8^(+)T cell function and decreasing MDSCs infiltration.This is the first study to develop peptides to block VISTA/PSGL-1 interaction,which could act as promising candidates for cancer immunotherapy.展开更多
基金supported by grants from the National Natural Science Foundation of China (U1904147,U20A20369)Shenzhen Science and Technology Program (KQTD20190929173853397,China)“Pearl River Talent Plan”Innovation and Entrepreneurship Team Project of Guangdong Province (2019ZT08Y464,China)。
文摘Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients.Here,we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells,especially myeloid derived suppressor cells(MDSCs)and CD8^(+)T cells.Then,peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique,and its mutant peptide VS3 was obtained by molecular docking based mutation.Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition,and elicit anti-tumor activity in vivo.The peptide DVS3-Pal was further designed by D-amino acid substitution and fatty acid modification,which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8^(+)T cell function and decreasing MDSCs infiltration.This is the first study to develop peptides to block VISTA/PSGL-1 interaction,which could act as promising candidates for cancer immunotherapy.
