VISTA is an acidic pH-selective ligand for PSGL-1

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Co-inhibitory immune receptors like CTLA-4 and PD-1 contribute to T cell dysfunction in cancer.
• Current therapies targeting CTLA-4 and PD-1 show efficacy but do not fully restore anti-tumor immunity.
• The mechanisms by which tumors create an immunosuppressive environment are not completely understood.

Purpose of the Study:

• To investigate the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) in T cell suppression within the tumor microenvironment.
• To identify the molecular interactions and environmental factors mediating VISTA-driven immune suppression.
• To explore VISTA as a potential therapeutic target for enhancing anti-tumor immunity.

Main Methods:

• Characterization of VISTA's interaction with T cells under varying pH conditions.
• Identification of key amino acid residues involved in VISTA-PSGL-1 binding.
• Development and testing of blocking antibodies targeting the VISTA-PSGL-1 interaction in acidic environments.
• In vivo assessment of antibody efficacy in reversing VISTA-mediated immune suppression.

Main Results:

• VISTA selectively engages and suppresses T cells at acidic pH, characteristic of tumor microenvironments.
• Specific histidine residues on VISTA mediate binding to P-selectin glycoprotein ligand-1 (PSGL-1).
• Antibodies designed to block VISTA-PSGL-1 interaction in acidic conditions effectively reversed VISTA-mediated immune suppression in vivo.

Conclusions:

• VISTA utilizes acidic pH in the tumor microenvironment to suppress T cell activity via PSGL-1 engagement.
• The VISTA-PSGL-1 interaction, modulated by pH, represents a novel mechanism of tumor-induced immune resistance.
• Targeting the pH-dependent VISTA-PSGL-1 axis offers a promising strategy for overcoming immune evasion in cancer therapy.