Design of a novel chimeric peptide via dual blockade of CD47/SIRPα and PD-1/PD-L1 for cancer immunotherapy

• Published in: Science China. Life sciences 2023-10, Vol.66 (10), p.2310-2328
• Main Authors: Hu, Zheng, Li, Wanqiong, Chen, Shaomeng, Chen, Danhong, Xu, Ran, Zheng, Danlu, Yang, Xin, Li, Shuzhen, Zhou, Xiuman, Niu, Xiaoshuang, Xiao, Youmei, He, Zhuoying, Li, Huihao, Liu, Juan, Sui, Xinghua, Gao, Yanfeng
• Format: Article
• Language: English
• Subjects: Antitumor activity; Antitumor agents; Biomedical and Life Sciences; Cancer; Cancer immunotherapy; CD8 antigen; Cell activation; Immune checkpoint inhibitors; Immunotherapy; Life Sciences; Lymph nodes; Lymphocytes T; Macrophages; Palmitic acid; PD-1 protein; PD-L1 protein; Peptides; Phagocytosis; Research Paper; Toxicity; Tumor cells; Tumors; γ-Interferon
• ISSN: 1674-7305; 1869-1889
• DOI: 10.1007/s11427-022-2285-6

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 SIRPα on 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/SIRPα blocking 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-γ in 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/SIRPα and 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.