Portraying the dark side of endogenous IFN-λ for promoting cancer progression and immunoevasion in pan-cancer

摘要

Background IFN-lambda has been shown to have a dual function in cancer, with its tumor-suppressive roles being wellestablished. However, the potential existence of a negative ''tumor-promoting'' effect of endogenous IFN-. is still not fully understood. @@@ Methods We conducted a comprehensive review and analysis of the perturbation of IFN-lambda genes across various cancer types. Correlation coefficients were utilized to examine the relationship between endogenous IFN-lambda expression and clinical factors, immune cell infiltration, tumor microenvironment, and response to immunotherapy. Genes working together with IFN-lambda were obtained by constructing the correlation-based network related to IFN-lambda and the gene interaction network in the KEGG pathway and IFN-lambda-related genes obtained from the networks were integrated as candidate markers for the prognosis model. We then applied univariate and multivariate COX regression models to select cancer-specific independent prognostic markers associated with IFN-lambda and to investigate risk factors for these genes by survival analysis. Additionally, computational methods were used to analyze the transcriptome, copy number variations, genetic mutations, and methylation of IFN-.-related patient groups. @@@ Result Endogenous expression of IFN-lambda has been linked to poor prognosis in cancer patients, with the genes IFN-lambda 2 and IFN-lambda 3 serving as independent prognostic markers. IFN-lambda acts in conjunction with related genes such as STAT1, STAT2, and STAT3 to affect the JAK-STAT signaling pathway, which promotes tumor progression. Abnormalities in IFN-lambda genes are associated with changes in immune checkpoints and immune cell infiltration, which in turn affects cancerand immune-related pathways. While there is increased immune cell infiltration in patients with IFN-lambda expression, this does not improve survival prognosis, as T-cell dysfunction and an inflammatory environment are also present. The amplification of IFNL2 and IFNL3 copy number variants drives specific endogenous expression of IFN-lambda in patients, and those with this specific expression have been found to have more mutations in the TP53 gene and lower levels of DNA methylation. @@@ Conclusion Our study integrated multi-omics data to provide a comprehensive insight into the dark side of endogenous IFN-lambda, providing a fundamental resource for further discovery and therapeutic exploration in cancer.

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