Integrated analysis of inflammatory response subtype-related signature to predict clinical outcomes, immune status and drug targets in lower-grade glioma

• Main Authors: Yudong Cao (Author), Hecheng Zhu (Author), Quan Chen (Author), Hailong Huang (Author), Dongcheng Xie (Author), Xuewen Li (Author), Xingjun Jiang (Author), Caiping Ren (Author), Jiahui Peng (Author)
• Format: Book
• Published: Frontiers Media S.A., 2022-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2022.914667
• Keywords: lower-grade glioma; inflammatory response; immune characteristics; prognostic signature; drug targets; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 13 (2022)

Background: The inflammatory response in the tumor immune microenvironment has implications for the progression and prognosis in glioma. However, few inflammatory response-related biomarkers for lower-grade glioma (LGG) prognosis and immune infiltration have been identified. We aimed to construct and identify the prognostic value of an inflammatory response-related signature, immune infiltration, and drug targets for LGG.Methods: The transcriptomic and clinical data of LGG samples and 200 inflammatory response genes were obtained from public databases. The LGG samples were separated into two inflammatory response-related subtypes based on differentially expressed inflammatory response genes between LGG and normal brain tissue. Next, inflammatory response-related genes (IRRGs) were determined through a difference analysis between the aforementioned two subtypes. An inflammatory response-related prognostic model was constructed using IRRGs by using univariate Cox regression and Lasso regression analyses and validated in an external database (CGGA database). ssGSEA and ESTIMATE algorithms were conducted to evaluate immune infiltration. Additionally, we performed integrated analyses to investigate the correlation between the prognostic signature and N 6-methyladenosine mRNA status, stemness index, and drug sensitivity. We finally selected MSR1 from the prognostic signature for further experimental validation.Results: A total of nine IRRGs were identified to construct the prognostic signature for LGG. LGG patients in the high-risk group presented significantly reduced overall survival than those in the low-risk group. An ROC analysis confirmed the predictive power of the prognostic model. Multivariate analyses identified the risk score as an independent predictor for the overall survival. ssGSEA revealed that the immune status was definitely disparate between two risk subgroups, and immune checkpoints such as PD-1, PD-L1, and CTLA4 were significantly expressed higher in the high-risk group. The risk score was strongly correlated with tumor stemness and m6A. The expression levels of the genes in the signature were significantly associated with the sensitivity of tumor cells to anti-tumor drugs. Finally, the knockdown of MSR1 suppressed LGG cell migration, invasion, epithelial-mesenchymal transition, and proliferation.Conclusion: The study constructed a novel signature composed of nine IRRGs to predict the prognosis, potential drug targets, and impact immune infiltration status in LGG, which hold promise for screening prognostic biomarkers and guiding immunotherapy for LGG.