Ye Wenrui, Luo Cong, Liu Fangkun, Liu Zhixiong, Chen Fenghua
Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China.
Clinical Medicine Eight-year Program, Xiangya Medical School of Central South University, Changsha, China.
Front Oncol. 2021 Feb 19;11:634617. doi: 10.3389/fonc.2021.634617. eCollection 2021.
Immunotherapy 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.
HPA, 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.
In 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, < 0.001). The opposite association was significantly observed in skin cutaneous melanoma (SKCM) cohort (OS, HR = 0.96, 95% CI = 0.94-0.98, < 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.
CD96 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.
免疫疗法显著改善了患者的预后，但最近遇到了障碍。CD96是一种在T细胞和自然杀伤（NK）细胞上表达的新型免疫检查点，对调节免疫功能至关重要。然而，在泛癌中CD96如何与免疫浸润和患者预后相关仍不清楚。
使用HPA、TCGA、GEO、GTEx、Oncomine、TIMER2.0、PrognoScan、Linkedomics、Metascape和GEPIA2数据库分析癌症中的CD96。数据可视化大多通过R语言4.0.2版实现。
总体而言，大多数癌症组织与相邻正常组织之间CD96表达存在差异。CD96显著影响多种癌症的预后。特别是，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）和疾病特异性生存期（DSS）相关（OS，HR = 2.18，95%CI = 1.79 - 2.66，P < 0.001）。在皮肤黑色素瘤（SKCM）队列中观察到相反的关联（OS，HR = 0.96，95%CI = 0.94 - 0.98，P < 0.001）。值得注意的是，SKCM样本在所有癌症类型中显示出最高的CD96突变频率。此外，在大多数癌症中，CD96表达水平与公认的免疫检查点表达水平以及包括CD8 + T细胞、树突状细胞（DC）、巨噬细胞、单核细胞、NK细胞、中性粒细胞、调节性T细胞（Treg）和滤泡辅助性T细胞（Tfh）在内的多种免疫浸润细胞的丰度显著相关。在LGG、SKCM和肾上腺皮质癌（ACC）中，CD96分别被确定为危险因素、保护因素和无关变量。LGG中与CD96相关的基因参与白细胞的负调控，而在SKCM中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，它在SKCM中与1型辅助性T细胞（Th1）标志物强烈相关，但在LGG或ACC中均不相关。
CD96参与多种免疫反应，控制免疫细胞浸润，并影响各种癌症类型的恶性特性，因此可作为确定多种癌症尤其是胶质瘤和黑色素瘤患者预后和免疫浸润的潜在生物标志物。
