Abstract
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.
Highlights
In the past few decades, cancer has gradually become the top killer threatening human health [1]
The opposite association was significantly observed in skin cutaneous melanoma (SKCM) cohort (OS, hazard ratio (HR) = 0.96, 95% confidence intervals (95% CI) = 0.94–0.98, P < 0.001)
CD96 participates in diverse immune responses, governs immune cell infiltration, and impacts malignant properties of various cancer types, standing as a
Summary
In the past few decades, cancer has gradually become the top killer threatening human health [1]. Co-inhibitory or immune checkpoint receptors, such as cytotoxic T lymphocyte associated protein 4 (CTLA-4) and programmed death-1 (PD-1), are expressed on immune cells to limit the immune responses, and prevent immune-driven pathology. Immunotherapies blocking these receptors have shown tremendous success in the treatment of several cancers. The dilemma has attracted attention to exploring new immune checkpoints that can be safely targeted with high anti-tumor efficacy in malignancies, with the hope that targeting more co-inhibitory receptors will lead to higher response rates and better therapeutic outcomes. How CD96 correlating with immune infiltration and patient prognosis in pan-cancer remains unclear
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