Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy.

Xiaoshuang Niu; Menghan WU; Guodong LI; Xiuman Zhou; Wenpeng Cao; Wenjie Zhai; Aijun WU; Xiaowen Zhou; Shengzhe Jin; Guanyu Chen; Yanying LI; Jiangfeng DU; Yahong WU; Lu Qiu; Wenshan Zhao; Yanfeng Gao

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Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy.

Author: Xiaoshuang NIU ¹ ; Menghan WU ¹ ; Guodong LI ¹ ; Xiuman ZHOU ² ; Wenpeng CAO ¹ ; Wenjie ZHAI ¹ ; Aijun WU ¹ ; Xiaowen ZHOU ¹ ; Shengzhe JIN ¹ ; Guanyu CHEN ² ; Yanying LI ¹ ; Jiangfeng DU ¹ ; Yahong WU ¹ ; Lu QIU ² ; Wenshan ZHAO ¹ ; Yanfeng GAO ²
Author Information

1. School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
2. School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
Publication Type:Journal Article
Keywords: Cancer immunotherapy; Immune checkpoint; MDSC; PSGL-1; Peptide; Phage displayed bio-panning; T cell; VISTA
From: Acta Pharmaceutica Sinica B 2023;13(11):4511-4522
CountryChina
Language:English
Abstract: 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.