Population-based Multiomics Systematic Analysis Of The Role Of Endogenous IFN-λ In Cancer Progression And Immune Evasion

IFN-λ is a type III interferon with multiple biological functions that help to shape both innate and adaptive immune responses.Recent studies have shown that IFN-λ plays a dual role in cancer,and the molecular mechanism of exogenous IFN-λhas been relatively clear for the treatment of cancer.However,the negative role for the endogenous IFN-λ in cancer progression remains unclear.Objectives: This topic integrates the human ligand receptor genes and uses gene expression data to identify the IFN-λ receptor genes specifically expressed in tumors,with a systematic analysis of their negative role in tumor progression.Identified a significant correlation between IFN-λ tumor-specific expression and poor patient prognosis.We divided cancer patients into different groups by IFN-λ expression and systematically their and clinicopathological features to identify its molecular mechanisms in cancer progression,provide new insights into the progression of endogenous IFN-λ in cancer,and provide different perspectives for establishing new therapeutic strategies.Methods: First,the genomic and transcriptomic data of pan-cancer patients were downloaded from the Tumor Cancer Atlas(TCGA),and the ligand receptor data were obtained from the Cell Talk DB database,the specific expression of ligand receptor gene was systematically analyzed,and the specifically expressed IFN-λ gene was identified.Tumor-specific expression patterns of the IFN-λ gene were explored using consensus clustering methods.Second,multivariate Cox regression analysis was performed to determine whether IFN-λ2 and IFN-λ3 were independent predictors.A systematic dissection of IFN-λ-related gene expression changes in terms of receptor-ligand interaction,protein-protein interaction,and transcriptional regulation to identify the molecular mechanisms of IFN-λ tumor-tumor.Subsequently,the association of IFN-λ with the immune cells in the tumor microenvironment was explored using immune cell infiltration abundance data,and the association between IFN-λ expression and treatment response in cancer patients was investigated combined with immunotherapy data to explore the potential value of IFN-λ in cancer treatment.Finally,relevant differences in epigenetic,genomic variation,and gene expression status among IFN-λ patients were studied to identify the molecular mechanisms by which IFN-λ promotes tumor progression.Results: The study found that the tumor-specific expression pattern of the IFN-λgene was significantly associated with patient prognosis,and the IFN-λ gene could serve as an independent predictor of survival outcomes(HR=2.20).From the perspective of receptor-ligand interactions,protein-protein interactions,and transcriptional regulation,it was found that IFN-λ and related genes collectively promoted cancer development.Endogenous IFN-λ expression promoted the activation of the JAK/STAT signaling pathway by stimulating the ligand/receptor complex,initiating the phosphorylation of transcriptional activators(STAT1,STAT2,STAT3,STAT5),driving the expression of interferon-stimulated genes(ISGs)and molecular inflammatory mechanisms,affecting cell-cell adhesion,and participating in the regulation of immune function,thereby promoting cancer progression.In addition,it was inferred that there was a positive correlation between IFN-λ expression and the infiltration levels of natural killer T cells,CD8+ T cells,and M1-type macrophages,while a negative correlation was observed with the infiltration levels of T cells and other cells,indicating that patients expressing IFN-λ had a higher level of immune cell infiltration,corresponding to an immunologically activated phenotype,and had immunotherapy advantages.However,due to the presence of T cell dysfunction and a high-inflammatory environment,patients had poor prognosis.Subsequently,a multi-omics study was conducted on IFN-λ intergroup patients,and it was found that patients expressing endogenous IFN-λ had significantly amplified copy numbers of the IFN-λ2 and IFN-λ3 genes,indicating that changes in IFN-λ copy number itself drove the specific expression of the IFN-λ gene in patients,and that patients expressing endogenous IFN-λ had more TP53 gene mutations and lower DNA methylation levels.Finally,a prognostic model and classifier were constructed based on the identified IFN-λ-related genes,which showed good performance(AUC>0.8).These findings provide a deeper understanding of the negative role of IFN-λ in tumors and provide a theoretical basis for developing more effective treatment strategies.Conclusions: This study used human ligand receptor genes and pan-cancer gene expression data to identify the tumor-specific expression of the IFN-λ gene,and further research found that endogenous IFN-λ expression affects the expression of related genes,which collectively promote the occurrence and development of cancer.Through multi-omics analysis of IFN-λ intergroup patients,a wide range of copy number variations and transcriptome changes were found in IFN-λ in tumors,indicating that IFN-λ expression plays an important role in cancer.In summary,through multi-omics systematic analysis,we identified the negative role of endogenous IFN-λ in cancer development,providing a foundation for further exploration of cancer treatment.