Differentially Infiltrated Identification of Novel Diagnostic Biomarkers Associated with Immune Infiltration in Nasopharyngeal Carcinoma

Abstract

Background. The prognostic value of tumor-infiltrating immune cells has been widely studied in nasopharyngeal carcinoma (NPC). However, the role of tumor-infiltrating immune cells in the diagnosis of NPC has not been fully elucidated. Thus, tumor-infiltrating immune cell-related biomarkers in the diagnosis of NPC patients were explored in the current study. Methods. Gene expression profiles of NPC patients were downloaded from the Gene Expression Omnibus (GEO) database. Differentially infiltrating immune cells (DDICs) between NPC and control samples were analyzed by the CIBERSORT algorithm. Weighted gene coexpression network analysis (WGCNA) was performed to screen hub genes significantly correlated with DDIC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of hub genes were performed with R package clusterProfiler. The diagnostic value of hub genes was evaluated by receiver operating characteristic (ROC) curves. RT-qPCR was conducted to validate the expression patterns of diagnostic markers in NPC and adjacent control tissues. The correlations between diagnostic markers and immunomodulators were analyzed using the TISIDB. The protein-protein interaction (PPI) network based on immunomodulators significantly associated with diagnostic biomarkers was constructed and visualized by STRING. The functional enrichment analysis of genes in the PPI network was analyzed by the WebGestalt online tool. Results. The abundances of memory B cells, plasma cells, follicular helper T cells, activated NK cells, M0 macrophages, M1 macrophages, M2 macrophages, resting mast cells, and activated mast cells were significantly different between NPC and control samples. Dark orange was identified as the hub module, with a total of 371 genes associated with memory B cells, plasma cells, and M0 and M1 macrophages defined as hub genes, which were enriched into immune-related biological processes and pathways. FCER2, KHDRBS2, and IGSF9 were considered diagnostic biomarkers with areas under ROC curves as 0.985, 0.978, and 0.975, respectively. Moreover, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) suggested that the expression patterns of FCER2, KHDRBS2, and IGSF9 were consistent with the results in GEO datasets. TISIDB analysis revealed that FCER2, KHDRBS2, and IGSF9 had a strong association with 8 immunoinhibitors (BTLA, CD160, CD96, LAG3, PDCD1, TIGIT, CD244, and TGFB1) and 11 immunostimulators (CD27, CD28, CD40LG, CD48, ICOS, KLRC1, KLRK1, TMIGD2, TNFRSF13C, CXCR4, and C10 or f54). The PPI network implied that these 19 immunomodulators had interactions with other 50 genes. WebGestalt analysis demonstrated that 69 genes in the PPI network were enriched into cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, and pathways in cancer. Conclusion. Our study identified novel diagnostic biomarkers and revealed potential immune-related mechanisms in NPC. These findings enlighten the investigation of the molecular mechanisms of tumor-infiltrating immune cells regulating NPC.

Association between novel genetic variants of Notch signaling pathway genes and survival of hepatitis B virus‐related hepatocellular carcinoma

“…This gene was the first confirmed diagnostic marker related to immune cell infiltration in nasopharyngeal carcinoma. 37 Our study indicated that FCER2 rs1990975 T allele may reduce the risk of death in the HBV‐related HCC patients by upregulating the mRNA expression levels of FCER2 . In addition, the expression levels of FCER2 mRNA were decreased in the HCC tissues and higher mRNA expression levels were associated with a better survival.…”

“…In a nasopharyngeal carcinoma study, it was found that FCER2 was a downregulated gene in nasopharyngeal carcinoma, and its expression levels were significantly lower in nasopharyngeal carcinoma than in adjacent tissues. This gene was the first confirmed diagnostic marker related to immune cell infiltration in nasopharyngeal carcinoma 37 . Our study indicated that FCER2 rs1990975 T allele may reduce the risk of death in the HBV‐related HCC patients by upregulating the mRNA expression levels of FCER2 .…”

The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma

“…Chen and colleagues found that NK cells were enriched in the tumor stroma, with lower infiltration in the tumor epithelial nests [48]. Studies have also indicated that compared with nonmalignant nasopharyngeal biopsies, NK cells showed an increased trend in EBV + NPC tissue [62,63]. Unfortunately, these studies have not indicated NK cell subtypes.…”

“…[48,64] CD96-PVR interaction was detected between NK and tumor cells in NPC CD96 TIGIT and CD96 were positively correlated with FCER2 and KHDRBS2 and negatively correlated with IGSF9 in NPC *. [63] LAG3 Gal-3…”

Machine learning to comprehensively reveal signature genes and regulatory mechanisms in pituitary tumors

“…The value of the obtained genes as diagnostic markers was veri ed in the cohort of the training and validation sets by drawing receiver operating characteristic (ROC) curves for the above-mentioned intersection sets [9], and the diagnostic value was determined by using P < 0.05 as the threshold. The area under the ROC curve (AUC) was calculated, and the value of AUC ranged from 0 to 1.…”