The role of IFNLR1 in modulating T cell infiltration and cancer progression in renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, but reliable biomarkers for prognosis and immunotherapy response are lacking. We analyzed type III interferon (IFN-λ) and its receptor IFNLR1 expression in ccRCC versus normal tissues using TCGA and GEO datasets, with IFNLR1 protein levels validated by tissue microarray. We investigated correlations between IFNLR1 and clinical features, prognosis, CD4 + /CD8 + T-cell infiltration, and programmed cell death-ligand 1 (PD-L1) expression. In vitro experiments examined IFN-λ effects on ccRCC cell lines, while in vivo studies utilized IFNLR1-modulated mouse RENCA cell lines to assess tumor growth, immune microenvironment composition, and response to anti-PD1 therapy. In ccRCC, IFN-λ expression is elevated while IFNLR1 is significantly reduced compared to normal tissues, as confirmed by tissue microarrays. Lower IFNLR1 levels correlate with advanced tumor stage, poor grade, and worse prognosis, and show positive association with CD4 + /CD8 + T-cell infiltration and PD-L1 expression. In vitro, IFN-λ upregulates major histocompatibility complex (MHC) class I, chemokines, and PD-L1 in ccRCC cells. In vivo, RENCA tumors with reduced IFNLR1 expression exhibit faster growth, diminished T-cell infiltration, and impaired T-cell function, whereas tumors overexpressing IFNLR1 grow slower, respond better to anti-PD1 therapy, and show enhanced functional T-cell infiltration. IFNLR1 may serve as a potential prognostic biomarker for ccRCC, with its expression levels reflecting the tumor immune microenvironment. Its predictive value for clinical immunotherapy efficacy remains to be established in prospective clinical cohorts.