Table_1_CD96 Correlates With Immune Infiltration and Impacts Patient Prognosis: A Pan-Cancer Analysis.xlsx

BackgroundImmunotherapy has significantly improved patient outcomes, but encountered obstacles recently. CD96, a novel immune checkpoint expressed on T cells and natural killer (NK) cells, is essential for regulating immune functions. However, how CD96 correlating with immune infiltration and patient prognosis in pan-cancer remains unclear.
MethodsHPA, TCGA, GEO, GTEx, Oncomine, TIMER2.0, PrognoScan, Linkedomics, Metascape, and GEPIA2 databases were used to analyze CD96 in cancers. Visualization of data was mostly achieved by R language, version 4.0.2.
ResultsIn general, CD96 was differentially expressed between most cancer and adjacent normal tissues. CD96 significantly impacted the prognosis of diverse cancers. Especially, high CD96 expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) in the TCGA lower grade glioma (LGG) cohort (OS, HR = 2.18, 95% CI = 1.79–2.66, P < 0.001). The opposite association was significantly observed in skin cutaneous melanoma (SKCM) cohort (OS, HR = 0.96, 95% CI = 0.94–0.98, P < 0.001). Notably, SKCM samples demonstrated the highest CD96 mutation frequency among all cancer types. Furthermore, in most cancers, CD96 expression level was significantly correlated with expression levels of recognized immune checkpoints and abundance of multiple immune infiltrates including CD8+ T cells, dendric cells (DCs), macrophages, monocytes, NK cells, neutrophils, regulatory T cells (Tregs), and follicular helper T cells (Tfh). CD96 was identified as a risk factor, protective factor, and irrelevant variable in LGG, SKCM and adrenocortical carcinoma (ACC), respectively. CD96 related genes were involved in negative regulation of leukocyte in LGG, however, involved in multiple positive immune processes in SKCM. Furthermore, CD96 was significantly associated with particular immune marker subsets. Importantly, it strongly correlated with markers of type 1 helper T cell (Th1) in SKCM, but not in LGG or ACC either.
ConclusionsCD96 participates in diverse immune responses, governs immune cell infiltration, and impacts malignant properties of various cancer types, thus standing as a potential biomarker for determining patient prognosis and immune infiltration in multiple cancers, especially in glioma and melanoma.

背景：免疫治疗已显著改善了患者的预后，但近年来遭遇了诸多阻碍。CD96是一种新发现的表达于T细胞和自然杀伤（NK）细胞表面的免疫检查点（immune checkpoint），对免疫功能的调控至关重要。然而，CD96与泛癌中免疫浸润及患者预后的关联机制仍不明确。
方法：本研究采用HPA、TCGA、GEO、GTEx、Oncomine、TIMER2.0、PrognoScan、Linkedomics、Metascape及GEPIA2数据库，对CD96在癌症中的表达特征与调控作用进行分析。数据可视化主要通过R语言（版本4.0.2）完成。
结果：整体而言，CD96在多数癌组织与癌旁正常组织中存在差异表达。CD96对多种癌症的患者预后具有显著影响。具体而言，在TCGA低级别胶质瘤（LGG）队列中，CD96高表达与较差的总生存期（OS）及疾病特异性生存期（DSS）显著相关（OS：HR=2.18，95%CI=1.79–2.66，P<0.001）。而在皮肤黑色素瘤（SKCM）队列中则呈现相反的关联趋势（OS：HR=0.96，95%CI=0.94–0.98，P<0.001）。值得注意的是，SKCM样本的CD96突变频率在所有癌症类型中最高。此外，在多数癌症中，CD96的表达水平与公认的免疫检查点表达水平及多种免疫浸润细胞的丰度显著相关，包括CD8+ T细胞、树突状细胞（DCs）、巨噬细胞、单核细胞、NK细胞、中性粒细胞、调节性T细胞（Tregs）及滤泡辅助性T细胞（Tfh）。CD96在LGG中被鉴定为风险因子，在SKCM中为保护因子，而在肾上腺皮质癌（ACC）中则与预后无显著关联。CD96相关基因在LGG中参与白细胞的负向调控，而在SKCM中则参与多种正向免疫过程。此外，CD96与特定的免疫标志物亚群显著相关。重要的是，其在SKCM中与1型辅助性T细胞（Th1）的标志物强相关，但在LGG或ACC中并非如此。
结论：CD96参与多种免疫应答过程，调控免疫细胞浸润，并影响多种癌症的恶性生物学特性，因此有望成为多种癌症（尤其是胶质瘤与黑色素瘤）中评估患者预后及免疫浸润状态的潜在生物标志物。