Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy
Xiaoshuang Niu1,2, Menghan Wu1, Guodong Li1
1School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
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.
Insights
Researchers developed novel peptides to block the VISTA immune checkpoint, showing promise for cancer immunotherapy by enhancing T cell function and reducing suppressive myeloid cells.
Area of Science:
- Immunology
- Oncology
- Drug Discovery
Background:
- Cancer immunotherapy faces challenges with low response rates to PD-1/PD-L1 blockade.
- The immune checkpoint VISTA is highly expressed on tumor-infiltrating immune cells, including myeloid-derived suppressor cells (MDSCs) and CD8+ T cells.
Purpose of the Study:
- To develop novel peptide agents targeting the VISTA immune checkpoint for cancer immunotherapy.
- To investigate the anti-tumor activity and mechanisms of VISTA-blocking peptides.
Main Methods:
- Phage display bio-panning was used to develop peptide C1 with VISTA binding affinity.
- Molecular docking guided mutation to create peptide VS3, which binds VISTA and blocks PSGL-1 interaction under acidic conditions.
- Peptide DVS3-Pal was engineered with d-amino acid substitution and fatty acid modification for enhanced stability and efficacy.
Main Results:
- Peptide VS3 demonstrated high affinity binding to VISTA and inhibited VISTA/PSGL-1 interaction.
- VS3 elicited anti-tumor activity in vivo.
- The modified peptide DVS3-Pal showed enhanced proteolytic stability and significant anti-tumor effects by boosting CD8+ T cell function and reducing MDSC infiltration.
Conclusions:
- This study presents the first peptides designed to block the VISTA/PSGL-1 interaction.
- These peptides, particularly DVS3-Pal, represent promising therapeutic candidates for enhancing cancer immunotherapy.
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