A Cleveland Clinic-led study found that the immune checkpoint protein VISTA can deactivate tumor-fighting T cells during immunotherapy, leading to resistance. Published in Science Immunology, the research reveals VISTA binds to the LRIG1 protein in T cells, a protein previously linked to bone and fat development. This binding suppresses T-cell replication, survival, and function by sending inhibitory signals.
The team’s preclinical work indicates that blocking LRIG1 could halt tumor growth in various cancers. They discovered that LRIG1 expression in tumor-associated T cells correlated with immunotherapy resistance in human melanoma and endometrial cancer.
Li Lily Wang, Ph.D., explained that VISTA modulates immune responses to prevent autoimmune issues but impairs immune activation during immunotherapy, hindering T cells from attacking cancer cells. Pharmaceutical efforts to block VISTA have struggled due to limited understanding of its mechanisms.
Wang’s earlier studies showed VISTA also promotes myeloid-derived suppressor cells (MDSCs), which block T cell function. Combined, these findings suggest VISTA is a major obstacle in effective antitumor responses during cancer treatments.
As reported by Medical Xpress, Wang emphasized the need for drug developers to consider these insights to enhance treatment response rates. Hieu Minh Ta, Ph.D., the study’s lead author, highlighted that understanding LRIG1’s role could improve clinical outcomes for patients unresponsive to current therapies.
The research, a collaboration between Dr. Wang, Timothy Chan, MD, Ph.D, and other clinicians, noted that patients resistant to immunotherapy had higher LRIG1 levels in their T cells. The team is now exploring the VISTA/LRIG1 axis in various cancers, aiming to combine VISTA-specific inhibitors with existing therapies to reduce resistance and improve survival.