Pan-cancer analysis of co-inhibitory molecules revealing their potential prognostic and clinical values in immunotherapy.

Background: The widespread use of immune checkpoint inhibitors (anti-CTLA4 or PD-1) has opened a new chapter in tumor immunotherapy by providing long-term remission for patients. Unfortunately, however, these agents are not universally available and only a minority of patients respond to them. Therefore, there is an urgent need to develop novel therapeutic strategies targeting other co-inhibitory molecules. However, comprehensive information on the expression and prognostic value of co-inhibitory molecules, including co-inhibitory receptors and their ligands, in different cancers is not yet available. Methods: We investigated the expression, correlation, and prognostic value of co-inhibitory molecules in different cancer types based on TCGA, UCSC Xena, TIMER, CellMiner datasets. We also examined the associations between the expression of these molecules and the extent of immune cell infiltration. Besides, we conducted a more in-depth study of VISTA. Result: The results of differential expression analysis, correlation analysis, and drug sensitivity analysis suggest that CTLA4, PD-1, TIGIT, LAG3, TIM3, NRP1, VISTA, CD80, CD86, PD-L1, PD-L2, PVR, PVRL2, FGL1, LGALS9, HMGB1, SEMA4A, and VEGFA are associated with tumor prognosis and immune cell infiltration. Therefore, we believe that they are hopefully to serve as prognostic biomarkers for certain cancers. In addition, our analysis indicates that VISTA plays a complex role and its expression is related to TMB, MSI, cancer cell stemness, DNA/RNA methylation, and drug sensitivity. Conclusions: These co-inhibitory molecules have the potential to serve as prognostic biomarkers and therapeutic targets for a broad spectrum of cancers, given their strong associations with key clinical metrics. Furthermore, the analysis results indicate that VISTA may represent a promising target for cancer therapy.