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

Abstract

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.

• Authors: Zheng Hu, Wanqiong Li, Shaomeng Chen, Danhong Chen, Ran Xu, Danlu Zheng, Xin Yang, Shuzhen Li, Xiuman Zhou, Xiaoshuang Niu, Youmei Xiao, Zhuoying He, Huihao Li, Juan Liu, Xinghua Sui, Yanfeng Gao
• Journal: Science China. Life sciences (Sci China Life Sci) Vol. 66 Issue 10 Pg. 2310-2328 (10 2023) ISSN: 1869-1889 [Electronic] China
• PMID: 37115491 (Publication Type: Journal Article)
• Copyright: © 2023. Science China Press.

Chemical References

• Programmed Cell Death 1 Receptor
• CD47 Antigen
• B7-H1 Antigen
• CD47 protein, human

Topics

• Humans
• Animals
• Mice
• Programmed Cell Death 1 Receptor
• CD47 Antigen (genetics)
• B7-H1 Antigen
• Phagocytosis
• Immunotherapy
• Neoplasms (pathology)