A prognostic 19-gene signature and LBP-mediated immune dysregulation define the tumor microenvironment in poor-prognosis KIRC

TL;DR

This study identifies a 19-gene signature and the role of LBP in immune dysregulation in kidney cancer, offering a new tool to predict poor outcomes and potential therapeutic targets.

Contribution

A novel 19-gene prognostic signature and the functional role of LBP in immune dysregulation in KIRC are identified.

Findings

A 19-gene signature robustly distinguishes poor-prognosis KIRC patients with AUC values of 0.84 in TCGA and 0.79-1.00 in external datasets.

LBP promotes tumor-cell migration and macrophage activation, with neutralization reversing these effects.

Six immune-cell features, including M0 macrophages and regulatory T cells, are associated with survival outcomes.

Abstract

Kidney renal clear cell carcinoma (KIRC) exhibits pronounced immune heterogeneity, and immune dysregulation within the tumor microenvironment (TME) contributes to poor outcomes. Leveraging TCGA-KIRC RNA-seq, we stratified patients by immune-cell infiltration and immune-regulatory gene expression to define a poor-survival subgroup for discovery. Differential expression analysis prioritized lipopolysaccharide-binding protein (LBP) and generated an immune-relevant candidate set that was refined from 406 to 87 genes by stepwise logistic regression and then benchmarked through one million random 20-gene models, yielding a final 19-gene prognostic signature. Six immune-cell features associated with survival were identified, including higher M0 macrophages, regulatory T cells, activated CD4 memory T cells, plasma cells, and neutrophils (worse prognosis) and resting mast cells (better prognosis). LBP was highly expressed in the poor-survival subgroup and functionally validated in vitro: RT-PCR/ELISA/Western blot and cell-based assays showed that LBP promotes tumor-cell migration and macrophage activation, while LBP neutralization reversed these effects, supporting its role as a mediator of tumor-immune crosstalk. The 19-gene panel robustly distinguished poor-survival patients, achieving AUC = 0.84 in TCGA-KIRC and 0.79-1.00 across three external datasets. Pathway analysis implicated ERK signaling, immune suppression, and chronic inflammation. These findings establish a clinically relevant 19-gene signature and highlight LBP-driven immune dysregulation as a potential target in KIRC.

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