Previous studies found that CD58 is a glycoprotein expressed on the surface of B cells, T cells, monocytes, granulocytes and thymic epithelial cells, an important member of the immune superprotein family, and has a role in promoting cell adhesion [19]. We found that the main studies of CD58 focused mainly on hematological tumors[23–25, 27], skin diseases[35], where CD58 plays a rather important role through different mechanisms. There are also a few other malignant tumors, such as cervical cancer[28], colon cancer[29] and other tumors in which we found differential expression of CD58 with different implications for the development and prognosis of tumor patients. CD58 has not been extensively studied and some studies found that CD58 plays an immunomodulatory function. CD58 binds to its ligand CD2, promotes important adhesion between T cells and target cells and activates T cells[20]. The regulatory role of CD58 on other immune cells has not been systematically investigated and the expression of CD58 and its regulatory role on immune cells are not yet clear in hepatocellular carcinoma.
Here, we report the CD58 expression levels in different types of cancers and the impact of changes in CD58 expression levels on the prognosis of different types of cancers. We found that CD58 was meaningfully differentially expressed between hepatocellular carcinoma tumor tissues and normal tissues, with higher CD58 expression levels in hepatocellular carcinoma than in normal tissues. And we found that high CD58 expression was associated with a poorer prognosis in hepatocellular carcinoma. To further investigate the relationship between CD58 expression levels and the immune microenvironment in hepatocellular carcinoma on the prognosis of hepatocellular carcinoma, we investigated the association between CD58 expression levels and immune cells in the immune microenvironment as well as immune markers and we found that CD58 expression levels correlated with immune cell infiltration and immune marker levels. Thus, our study provides insights to understand the potential role of CD58 in tumor immunology and its application as a cancer biomarker.
In our study, we analyzed the differential expression levels of CD58 in various types of cancers in the TCGA database using two analytical methods TIMER and UALCAN. We found differential expression of CD58 in a variety of tumor tissues versus normal tissues. First, we used the TIMER database to find that CD58 had high expression levels in LIHC, THCA, HNSC, CHOL, KIRC, BRCA, ESCA, KIRP, GBM, STAD and CESC. Low level expression of CD58 was found in READ, LUSC, LUAD, KICH and other tumors. We analyzed TCGA RNA sequencing data using UALCAN with the following results: high expression of CD58 in CHOL, ESCA, GBM, HNSC, KIRC, KIRP, LIHC, PCPG, STAD, THCA and UCEC, low expression of CD58 was found in BRCA, KICH, LUAD, LUSC, PRAD and READ. We obtained consistent results that CD58 expression levels in hepatocellular carcinoma were higher than those in normal tissues.
By analyzing the prognostic impact of CD58 in various cancers in TCGA by Kaplan Meier plotter and GEPIA, we found a consistent correlation between CD58 expression in hepatocellular carcinoma prognosis. High CD58 expression often implies a poor prognosis for patients with hepatocellular carcinoma. The results of KM plotter found that in most tumor types LIHC, PAAD, PCPG, THYM, LUAD and HNSC, increased CD58 expression was associated with poor prognosis. Increased CD58 expression in UCES, BRCA, ESCA, SARC, OV and CESC was associated with a good prognosis. In GEPIA using data from TCGA and GTEx, we found that poor prognosis in GBM, LGG, LIHC, PAAD, UVM was associated with high CD58 expression, and in KIRC we found different results. The higher CD58 expression level, the worse prognosis of KIRC patients.
The differences in CD58 expression levels in various cancers and the relationship between expression levels and prognosis in different databases may be related to the way the data were collected, the way the data were processed, and the underlying biological characterization mechanisms. Here, we can clarify that CD58 can be used as a biomarker for prognosis in some tumors, including hepatocellular carcinoma, on which we focused our study.
Many studies have previously reported on immune regulation in hepatocellular carcinoma, and the immune microenvironment, including immune cells and immune gene markers in hepatocellular carcinoma has been carefully studied. In STRING, we found CD58 was closely related to immune and inflammatory processes. Previous studies have shown that poor or incomplete activation of CD4 + T and CD8 + T cells can cause immune tolerance in the liver[36]. Th2 CD4 + T helper cells exert some immunosuppressive function. High expression of Th2-type cytokines (IL-4, IL-5 and IL-10) has also been found to be associated with disease progression and metastasis in hepatocellular carcinoma. Th17 in hepatocellular carcinoma suppresses antitumor responses when co-cultured in vitro[37]. T-cell depletion is characterized by diminished pro-inflammatory responses upon stimulation, reduced cytokine production, impaired proliferation and reduced cytotoxic effects. There is evidence that depleted CD8 + T cells within the tumor and in the circulation are a characteristic of poor prognosis in hepatocellular carcinoma[38]. Hepatic suppressor B cells, regulatory T cells (Treg), neutrophils, immature dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) negatively affect immune rejection by regulating tumor-specific T cells, preventing the activation of effector T cells, and inhibiting immune surveillance. Tumor-associated macrophages (TAMs) and NK cells accelerate angiogenesis in the hepatic tumor microenvironment[6, 11].
Our study found that CD58 expression was significantly and positively correlated with CD4 + T cells, monocytes, macrophages and dendritic cells. It was also significantly correlated with CD58 and markers of immune cells such as monocytes, tumor-associated macrophages, M1 macrophages, M2 macrophages, dendritic cells, Th1, Th2, and Treg. We propose that CD58 expression in hepatocellular carcinoma is associated with immune escape related cells, such as monocytes, tumor-associated macrophages, dendritic cells, and Treg, and CD58 synergizes with these immune cells in hepatocellular carcinoma to antagonize the antitumor effects of effector T cells, thus driving tumor progression. Undeniably, we observed that CD58 expression was significantly correlated with the regulation of several markers of helper T cells (Th1, Th2, Tfh, and Th17), and CD58 expression was strongly correlated with helper T cells. These correlations may suggest that CD58 regulates T cell function in hepatocellular carcinoma by some potential mechanism. In our study, we observed that high CD58 expression correlated with the high level of immune infiltration of CD8 + T cells, CD4 + T cells, macrophages, neutrophils and DCs in a variety of tumors (especially hepatocellular carcinoma) and poor prognosis. CD58 has a close relationship with immune cells, but the mechanism of CD58 regulation of immune cells still needs further investigation.