Data Sheet 5_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.

背景：免疫检查点抑制剂（immune checkpoint inhibitors，涵盖抗CTLA4（anti-CTLA4）与抗PD-1（anti-PD-1）类药物）的广泛应用为患者带来长期缓解，开启了肿瘤免疫治疗的新篇章。然而遗憾的是，这类药物并非普遍适用，仅少数患者能从中获益。因此，亟需开发针对其他共抑制分子的新型治疗策略。但目前尚缺乏共抑制分子（包括共抑制受体及其配体）在不同癌症中的表达情况与预后价值的全面信息。
方法：本研究基于TCGA、UCSC Xena、TIMER及CellMiner数据集，探究了共抑制分子在不同癌种中的表达特征、相关性及其预后价值，并分析了这些分子的表达与免疫细胞浸润程度之间的关联。此外，我们还针对VISTA开展了更为深入的研究。
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与肿瘤预后及免疫细胞浸润显著相关。据此，我们认为这些分子有望作为特定癌症的预后生物标志物。此外，本研究分析还表明，VISTA发挥着复杂的调控作用，其表达水平与肿瘤突变负荷（Tumor Mutation 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密切关联。
结论：鉴于这些共抑制分子与关键临床指标存在强相关性，它们具备作为广谱癌症预后生物标志物与治疗靶点的潜力。此外，本研究分析结果提示，VISTA或可成为极具潜力的癌症治疗靶点。