Immune-related gene signature associates with immune landscape and predicts prognosis accurately in patients with Wilms tumour

Abstract

Wilms tumour (WT) is the most common kidney malignancy in children. Chemoresistance is the leading cause of tumour recurrence and poses a substantial therapeutic challenge. Increasing evidence has underscored the role of the tumour immune microenvironment (TIM) in cancers and the potential for immunotherapy to improve prognosis. There remain no reliable molecular markers for reflecting the immune landscape and predicting patient survival in WT. Here, we examine differences in gene expression by high-throughput RNA sequencing, focused on differentially expressed immune-related genes (IRGs) based on the ImmPort database. Via univariate Cox regression analysis and Lasso-penalized Cox regression analysis, IRGs were screened out to establish an immune signature. Kaplan-Meier curves, time-related ROC analysis, univariate and multivariate Cox regression studies, and nomograms were used to evaluate the accuracy and prognostic significance of this signature. Furthermore, we found that the immune signature could reflect the immune status and the immune cell infiltration character played in the tumour microenvironment (TME) and showed significant association with immune checkpoint molecules, suggesting that the poor outcome may be partially explained by its immunosuppressive TME. Remarkably, TIDE, a computational method to model tumour immune evasion mechanisms, showed that this signature holds great potential for predicting immunotherapy responses in the TARGET-wt cohort. To decipher the underlying mechanism, GSEA was applied to explore enriched pathways and biological processes associated with immunophenotyping and Connectivity map (CMap) along with DeSigN analysis for drug exploration. Finally, four candidate immune genes were selected, and their expression levels in WT cell lines were monitored via qRT-PCR. Meanwhile, we validated the function of a critical gene, NRP2. Taken together, we established a novel immune signature that may serve as an effective prognostic signature and predictive biomarker for immunotherapy response in WT patients. This study may give light on therapeutic strategies for WT patients from an immunological viewpoint.

Exploration of biological significance of m6A-related genes in Wilms tumor

“…Some studies have compared the differences of immune cells in tumor microenvironment between WT high-risk group and low-risk group. In the high-risk group, it was found that except for B cells and macrophage M1 type, other types of cells were lower than those in the low-risk group, including CD8 + naive T cells, CD8 + T cells, macrophage M2 type, mast cells, neutrophils, NKT cells and Treg cells [39]. This suggests that the high-risk WT tumor microenvironment as a whole exist immune inactivation and lack of T cells.…”

Identification of the Expression Patterns and Potential Prognostic Role of m6A-RNA Methylation Regulators in Wilms Tumor

“…A large number of existing studies have shown that the tumor microenvironment can not only in uence tumor cell growth and metastasis, but also has great importance in therapy [39][40][41] , in particular, the association between TME and methylation modi cations and the in uence of TME on tumor progression in WT has been reported 42,43 . We quanti ed the in ltration of 29 different immune cell types in WT samples by ssGSEA analysis.…”

Bioinformatical analysis of the key differentially expressed genes for screening potential biomarkers in Wilms tumor

“…Their research suggested that impaired anti-tumor immunity may be responsible for the poor prognosis of WT patients at high risk. Research into the mechanisms that disrupt the anti-tumor immune response will contribute to the development of more effective treatments 66 .…”