VISTA Expression on Cancer-Associated Endothelium Selectively Prevents T-cell Extravasation

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Cancers employ mechanisms like immune checkpoint molecule upregulation to evade T-cell immunity.
• The role of immune checkpoint molecules on tumor endothelial cells remains less understood compared to tumor cells and leukocytes.

Purpose of the Study:

• To investigate the expression and function of V-domain Ig suppressor of T-cell activation (VISTA) on endothelial cells.
• To determine the impact of endothelial VISTA on T-cell infiltration and its correlation with cancer prognosis.

Main Methods:

• Analysis of VISTA expression on endothelial cells in patient tumor samples (synovial sarcoma, carcinomas) and immune-privileged tissues.
• Utilized an ex vivo human vasculature model to assess VISTA's effect on T-cell transmigration under physiologic flow.
• Investigated VISTA regulation by cancer cell-secreted factors, including VEGF-A, and its subcellular localization.

Main Results:

• VISTA was highly expressed on endothelial cells in synovial sarcoma, carcinomas, and immune-privileged tissues.
• Endothelial VISTA selectively inhibited T-cell transmigration across endothelial layers without affecting other immune cells.
• Endothelial VISTA expression correlated with reduced intratumoral T-cell infiltration and poorer prognosis in metastatic synovial sarcoma.
• VEGF-A-dependent cancer cell-secreted factors upregulated endothelial VISTA expression.

Conclusions:

• Endothelial VISTA is a novel mechanism by which tumors can limit T-cell infiltration.
• Endothelial VISTA expression is regulated by cancer-secreted factors and impacts T-cell accessibility to tumors.
• Targeting endothelial VISTA may represent a new strategy for enhancing T-cell-mediated cancer immunotherapy.