Although it has been confirmed that IRGs play an important role in tumorigenesis and tumor progression, there is still a need to make a comprehensive genome-wide profiling research to determine the relationship between molecular biological functions and patient clinical characteristics . The integrated analysis in the present study provides a better understanding of the clinical characteristics of IRGs and clarifies the molecular biological functions of IRGs. Several IRGs have played an importantly role in the initiation and development of glioma, which may act as crucial biomarkers to assist in the diagnosis and treatment of patients. Furthermore, the risk score based on the seven survival-associated IRGs was used to measure the infiltration level of six type immune cells and assessed the OS of glioma patients.
Although biological technology and equipment have great progressed present, the underlying specific molecular mechanisms of IRGs in glioma still remains unclear. In previous studies, some researchers had explored the differential expression of several IRGs among different grades of glioma, and provided a novel and comprehensive perspective in the mechanism of glioma progression in the genetic molecule level [27, 28]. However, a system analysis has not been performed on the characteristics of IRGs in glioma, to date. Hence, the study of the tumor immune microenvironment is a crucial part for investigations on the immunotherapy of glioma.
Since alterations to the genome were associated with the invasive characteristics of tumor cells, focus was given on this analysis to clarify the potential relationships between the immunogenomic profile and immune microenvironment in tumors, which might connect with patient’s OS. The gene functional enrichment analysis in the present study demonstrated that these differentially expressed IRGs were mainly enriched in cytokine-cytokine receptor interactions and chemokine signaling pathways. The chemokine system actively participates in the development of central nervous system tumors and is involves in the pathogenesis of glioma. Furthermore, chemokines and their receptors were interrelated with chemotaxis, leukocyte infiltration, invasiveness and the promotion of glioma cell proliferation. The bioinformatics analysis demonstrated that the upregulation of IRGs could promote the initiation and development of glioma through the influence of some inflammatory cells and pathways.
In order to explore potential molecular mechanisms of IRGs, TFs regulated the network with IRGs were constructed to determine whether several crucial TFs could up-regulate or down-regulate the present hub IRGs. HOXC11, HOXC9, PAX3, ELF5, GATA4, HNF4A, HOXA9 and HOXB13 occupied a prominent position in this network. To data, no literature has been reported on the molecular biological functions of HOXC11, HOXC9, ELF5 and HNF4A in regulating the initiation of glioma, and the present study has provided limited information on the functions of other TFs in regulating glioma [29–31].
The risk score was chosen as a tool to monitor the immune microenvironment and suggested the OS in glioma patients. In addition, seven survival-associated IRGs (SSTR5, CXCL10, CCL13, SAA1, CCL21, CCL27 and HTR1A) were selected by the LASSO to calculate the risk score in TCGA dataset. Considering that the underlying molecular mechanism corresponding to the potential clinical value of these seven survival-associated IRGs, among these genes, SSTR5 is downregulated in glioma and inhibits glioma cell proliferation , while CXCL10、CCL20 is upregulated and promotes glioma cell proliferation [33–34]. SAA2 can increase migration and invasion behaviors of glioma cell . no literature has been reported on the molecular biological functions of HTR1A in glioma at present. Overall, these studies provided little information on the molecular biological functions of these survival-associated IRGs in glioma.
The nomogram has been extensively applied to calculate the clinical risk factors and predict clinical prognosis in many tumors, which has shown favorable effects [36, 37]. Hence, the risk score was connected with the clinical characteristics (grade, gender, age, IDH status, 1p/19q code), and a nomogram was constructed to prove that the risk score has a great performance in predicting the OS of glioma patients. In addition, the nomogram could also predict the 5-year survival rate in the differential risk score groups via the KM survival analysis. According to the nomogram established in the present study, the risk score based on seven survival-associated IRGs were demonstrated as an independent prognostic factor, which may provide new evidences for the treatment of glioma.
In order to explore the tumor-immune interactions, it is necessary to characterize the immune infiltration landscape. The relationship between risk score and level of immunocyte infiltration was established to determine the regulation mechanism of the immune microenvironment in GBM. In the present study, we demonstrated the infiltrations level of B_ cell and Neutrophil were evidently positively correlated with the risk score, while CD_4 T cell infiltration level was significantly negatively correlated with the risk score. These results indicated that the higher infiltration levels of B_ cell, Neutrophil and lower CD_4 T cell might be observed in high-risk patients.
These results suggested that immune cells played an important role in the pathogenesis of glioma, and it was also confirmed that the risk score could be regarded as a potential predictor for monitoring the infiltration level of immune cells. Previously, Ge J et al demonstrated that glioma patients had significantly upregulated frequencies of CD4 + cells, when compared to healthy controls . Sokratous G et al suggested that the infiltration level of cytotoxic T cell in glioma could importantly affect the clinical prognosis . However, the biological function of these immune cells in glioma has not be fully and comprehensive explored. The analysis in the present study can provide novel insights for solving several problems, and be a foundation for more in-depth and high-quality researches in the treatment of glioma patients.
There were still some limitations in the present research. First, the samples did not contain information about the excision scope of glioma that connected to a patient’s prognosis. Hence, the collection of more thorough and comprehensive information needs to be explored in the future. In addition, without verifying with an independent cohort, the credibility of these present research results remains to challenged. Furthermore, the lack of an in vitro or in vivo experiment was also a limitation of present study.