Targeting Vascular Endothelial-Cadherin in Tumor-Associated Blood Vessels Promotes T-cell-Mediated Immunotherapy

Area of Science:

• Oncology
• Immunology
• Vascular Biology

Background:

• T-cell infiltration into solid tumors correlates with better prognosis and immunotherapy response.
• Mechanisms governing CD8+ T-cell tumor infiltration and drugs to promote it remain largely undefined.
• VE-cadherin, an endothelial cell-specific protein, regulates vascular integrity and its downregulation is linked to tumor pathology.

Purpose of the Study:

• To investigate the role of VE-cadherin in T-cell infiltration into tumors.
• To develop and evaluate a therapeutic agent that modulates VE-cadherin for enhanced cancer immunotherapy.

Main Methods:

• Development of an oligonucleotide-based inhibitor (CD5-2) targeting the VE-cadherin/miR-27a interaction.
• Administration of CD5-2 to tumor-bearing mice to assess effects on tumor vasculature and T-cell infiltration.
• Evaluation of CD5-2 in combination with anti-PD-1 antibody therapy.

Main Results:

• CD5-2 treatment increased VE-cadherin expression in tumor endothelium, activating TIE-2 and tight junction pathways.
• Vessel structure and function were normalized in tumors treated with CD5-2.
• CD5-2 enhanced tumor-specific T-cell infiltration and CD8+ T-cell redistribution within the tumor.
• Combined CD5-2 and anti-PD-1 therapy showed enhanced anti-tumor efficacy.

Conclusions:

• VE-cadherin plays a critical role in facilitating T-cell infiltration into tumors.
• CD5-2 represents a potential therapeutic strategy to enhance cancer immunotherapy by targeting tumor vasculature.
• This study provides preclinical proof of concept for CD5-2 as a vascular-targeting agent to improve immunotherapy outcomes.