At present, the prognosis of patients with glioma is dismal despite current comprehensive treatment strategies, including surgery, radiation, and chemotherapy. The immune microenvironment has been reported to be related to the therapeutic resistance of glioma(Ma et al. 2018; Majd et al. 2020). Therefore, immunotherapeutic treatments, including adoptive immunotherapy, active specific immunotherapy, nonspecific immunotherapy and gene therapy, have been exploited to treat malignant gliomas(Simonelli et al. 2018; Reznik et al. 2018; Vismara et al. 2019). It is urgent to explore reliable prognostic biomarkers and personalized treatment strategies for glioma. Our results demonstrated that RNASE2 might act as a biomarker for prognosis and a target for immunotherapy.
In this study, we found that RNASE2 overexpression was observed in glioma tissues compared with normal brain tissues. Our results indicated that RNASE2 expression was significantly related to tumor grade. In addition, the correlation of RNASE2 expression with the survival of glioma patients was analyzed. The results showed that high RNASE2 expression is associated with a poor prognosis. We conducted univariate and multivariate Cox analyses to explore the prognostic significance of RNASE2. We identified and validated that the expression level of RNASE2 was an independent prognostic factor for prognosis.
To further explore the function of RNASE2 in glioma, GSEA was performed. GSEA showed that the systemic lupus erythematosus, graft versus host disease, allograft rejection, Leishmania infection, hematopoietic cell lineage KEGG pathways and immunoglobulin complex, humoral immune response mediated by circulating immunoglobulin, immunoglobulin complex circulating, immunoglobulin receptor binding, and antigen binding GO terms were differentially enriched in the high RNASE2 expression group. These results suggest that RNASE2 may play an important role in immune-related signaling pathways.
The results of functional analysis indicated that RNASE2 is closely related to immune-related signaling pathways. Therefore, we used the TIMER database to explore connections between RNASE2 expression and immune infiltration levels in glioma. We found that the expression of RNASE2 was positively associated with the infiltration levels of a wide variety of immune cells. However, DCs, neutrophils and macrophages exhibited the strongest correlations with RNASE2 expression. Moreover, ssGSEA indicated a substantial positive correlation between RNASE2 expression and the infiltration levels of immune cells, especially NK cells, macrophages, eosinophils and neutrophils. Our results indicate that RNASE2 plays an important role in regulating the glioma immune microenvironment.
Recent studies have revealed that TIICs have negative impacts on the prognosis of cancer patients(Zha et al. 2020; Qian et al. 2018; Powles et al. 2014). The central nervous system (CNS) has a unique immune microenvironment compared to other tumor microenvironments. CNS immune defenses are largely mediated by brain -resident macrophages and microglia. Glioma-infiltrating macrophages have been proven to participate in glioma-induced immune dysregulation, which facilitates the progression of the malignant process(Wei et al. 2020). Osteopontin is a key driver of macrophage infiltration, which can maintain the M2 macrophage gene signature and phenotype in glioma. Thus, macrophages are related to the negative influence of RNASE2 on glioma(Wei et al. 2019).
RNASE2 is a member of the RNase A superfamily. The RNASE2 signaling pathway in cancers is still poorly defined; however, several studies have proven that the RNase A superfamily is closely related to the occurrence and development of many cancers. PHF6 mutation leads to the accumulation of DNA damage in the cell by inhibiting the expression of RNASE1 in T-cell acute lymphoblastic leukemia(Wang et al. 2013), while overexpression of RNASE1 is correlated with poor survival in prostate cancer(Gao et al. 2020). Combination analysis of RNASE2 with other genes has independent prognostic value in many cancers(Xiang et al. 2020; Niini et al. 2002). RNase4 and RNase5 are mainly secreted from endothelial cells and have been reported to be associated with cancer(Wang et al. 2018; Yu et al. 2017). RNASE7 can promote hepatocellular carcinoma progression by activating ROS1 signaling(Liu et al. 2021). Based on our research results and those of previous studies on the RNase A superfamily, it is reasonable to believe that RNASE2 affects the progression of glioma.