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

Abstract

Background IFN-λ has been shown to have a dual function in cancer, with its tumor-suppressive roles being well-established. However, the potential existence of a negative ‘‘tumor-promoting’’ effect of endogenous IFN-λ is still not fully understood. Methods We conducted a comprehensive review and analysis of the perturbation of IFN-λ genes across various cancer types. Correlation coefficients were utilized to examine the relationship between endogenous IFN-λ expression and clinical factors, immune cell infiltration, tumor microenvironment, and response to immunotherapy. Genes working together with IFN-λ were obtained by constructing the correlation-based network related to IFN-λ and the gene interaction network in the KEGG pathway and IFN-λ-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-λ 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-λ-related patient groups. Result Endogenous expression of IFN-λ has been linked to poor prognosis in cancer patients, with the genes IFN-λ2 and IFN-λ3 serving as independent prognostic markers. IFN-λ 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-λ genes are associated with changes in immune checkpoints and immune cell infiltration, which in turn affects cancer- and immune-related pathways. While there is increased immune cell infiltration in patients with IFN-λ 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-λ 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-λ, providing a fundamental resource for further discovery and therapeutic exploration in cancer.

LncRNA H19 was a prognostic biomarker associated with immune infiltrates in stomach adenocarcinoma

“…In cancer patients, the increased copy number of IFNL2 and IFNL3 promotes the particular expression of endogenous IFN-λ. IFN-λ interacts with STAT1, STAT2, STAT3, and other related genes to cause downstream-related pathway disorders, comprising cytokine-cytokine receptor interaction and the JAK-STAT signaling pathway, thereby promoting tumor progression [48].…”

Interferons in Colorectal Cancer Pathogenesis and Therapy

“…An emerging body of data suggests, that IFNλ, like the other interferons, might also have pro-tumor effects in some settings. Endogenous expression of IFNλ has been linked to poor prognosis in cancer patients, with the genes that encode IFNλ2 and IFNλ3 serving as independent prognostic markers [ 45 ]. Increased immune cell infiltration has been observed in patients with elevated IFNλ expression, but has not been correlated with improved prognosis.…”