Effect of tryptophan–serotonin–kynurenine pathways on immune landscape and survival in clear cell renal cell carcinoma: TCGA-KIRC transcriptomic analysis.

Abstract

542 Background: Tryptophan metabolism regulates immune tolerance via the kynurenine (IDO1, TDO2) and serotonin (TPH1, HTRfamily) pathways. Kynurenine accumulation drives T-cell exhaustion, whereas serotonin signaling may enhance immune activation. Recent data suggest selective serotonin reuptake inhibitors (SSRIs) can augment immune checkpoint inhibitor (ICI) efficacy, yet the molecular underpinnings remain unclear in clear-cell renal cell carcinoma (cRCC). Methods: RNA-seq data and clinical information for TCGA-KIRC (Kidney Renal Clear Cell Carcinoma, n = 537) were obtained from UCSC Xena. Gene-set enrichment analysis (ssGSEA) quantified kynurenine and serotonin pathway activity. RNA-seq expression and clinical data for TCGA-KIRC (n = 537) were analyzed using single-sample gene-set enrichment analysis (ssGSEA) to quantify kynurenine and serotonin pathway activity. Immune marker genes (TIGIT, CD8A, CXCL10, PDCD1, LAG3, CTLA4) were correlated with pathway scores using Spearman’s ρ. Associations with overall survival (OS) were evaluated via Cox proportional-hazards models and Kaplan–Meier analyses. Results: The kynurenine pathway showed strong positive correlations with multiple checkpoint markers (CD8A ρ=0.35, PDCD1 ρ=0.30, LAG3 ρ=0.30, TIGIT ρ=0.37; all FDR < 0.001), suggesting association with an immune-inflamed but exhausted microenvironment. Conversely, the serotonin pathway exhibited inverse correlations with key inhibitory receptors (PDCD1 ρ=-0.21, CTLA4 ρ=-0.24, LAG3 ρ=-0.25; all FDR < 0.01), implying an immune-activated yet less exhausted phenotype. In survival analyses, high serotonin-pathway activity was associated with significantly longer OS (HR 0.06, 95% CI 0.005–0.75, p=0.03), while the kynurenine pathway trended toward improved outcome (HR 0.16, 95% CI 0.02–1.11, p=0.06). Conclusions: Transcriptomic activation of the serotonin pathway was linked to reduced expression of immune checkpoint receptors and improved survival in cRCC, whereas kynurenine activity correlated with immune exhaustion markers. Together, these findings suggest serotonin metabolism may define an immune-favorable, checkpoint-low state, potentially explaining emerging clinical observations of enhanced ICI response among patients receiving SSRIs. Correlation of kynurenine and serotonin pathway activity with immune checkpoint markers and overall survival in TCGA-KIRC. Pathway Survival HR (%95 CI) Survival p-values TIGIT CD8A CXCL10 PDCD1 LAG3 CTLA4 Kynurenine 0.16(0.02–1.11) 0.06 0.37 0.35 0.32 0.3 0.3 0.27 Serotonin 0.16(0.02–1.11) 0.03 -0.16 -0.13 -0.11 -0.21 -0.25 -0.24