Data Sheet 3_Pan-cancer analysis of co-inhibitory molecules revealing their potential prognostic and clinical values in immunotherapy.csv

BackgroundThe 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. MethodsWe 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. ResultThe 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. ConclusionsThese 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.研究背景：免疫检查点抑制剂（immune checkpoint inhibitors，含抗CTLA4或抗PD-1制剂）的广泛应用为肿瘤免疫治疗翻开了全新篇章，为诸多患者带来了长期缓解的可能。但遗憾的是，此类药物并非普遍适用，仅少数患者能对其产生应答。因此，亟需开发针对其他共抑制分子的新型治疗策略。然而，目前针对不同癌症中各类共抑制分子（含共抑制受体及其配体）的表达情况与预后价值的全面研究数据仍较为匮乏。 研究方法：本研究依托TCGA、UCSC Xena、TIMER及CellMiner数据集，系统探究了不同癌型中共抑制分子的表达水平、相关性及其预后价值；同时分析了此类分子的表达与免疫细胞浸润程度之间的关联；此外，本研究还针对VISTA开展了更为深入的专项分析。 研究结果：差异表达分析、相关性分析及药物敏感性分析结果显示，CTLA4、PD-1、TIGIT、LAG3、TIM3、NRP1、VISTA、CD80、CD86、PD-L1、PD-L2、PVR、PVRL2、FGL1、LGALS9、HMGB1、SEMA4A及VEGFA均与肿瘤预后及免疫细胞浸润情况密切相关。据此，我们认为上述分子有望成为特定癌症的预后生物标志物。此外，本研究分析发现VISTA发挥着复杂的调控作用，其表达水平与肿瘤突变负荷（Tumor Mutational Burden, TMB）、微卫星不稳定性（Microsatellite Instability, MSI）、癌细胞干性、DNA/RNA甲基化及药物敏感性均存在显著关联。 研究结论：鉴于此类共抑制分子与多项关键临床指标存在强相关性，它们有望成为广谱癌症的预后生物标志物与治疗靶点。此外，本研究分析结果表明，VISTA或可成为极具潜力的癌症治疗新靶点。