Elevated Preexisting Lymphocytic Infiltration in Tumor Stroma Predicts Poor Prognosis in Resectable Urothelial Carcinoma of the Bladder

AIMS: Lymphocytic infiltrates are predominantly distributed in the tumour stroma, and represents the tumour-related immune response. The aim of this study was to elucidate the prognostic value of stromal lymphocytic infiltrates (SLI) in resectable urothelial carcinoma of the bladder (UCB). METHODS AND RESULTS: The prognostic significance of SLI in UCB was assessed in a discovery cohort (n = 226; 60 deaths) and in a validation cohort (n = 417; 103 deaths). SLI was categorised into intense (≥50% SLI) and non-intense (<50% SLI). A multivariable Cox model was used to analyse the associations of SLI score with overall survival (OS) and disease-free survival. Immunofluorescence staining was used to examine the composition and phenotypes of SLI. The median follow-up times were 58.1 and 64.9 months in the discovery and validation cohorts, respectively. SLI was intense in 38.1% of patients in the discovery cohort and in 20.9% of patients in the validation cohort (P < 0.001). SLI score had independent prognostic value for OS [hazard ratio (HR) 2.132; P = 0.016] and disease-specific survival (DSS) (HR 1.952; P = 0.04) in the discovery cohort, which was confirmed in the validation cohort (OS: HR 1.636; P = 0.023; DSS: HR 1.627; P = 0.029). SLI score was positively associated with histological grade, tumour stage and lymph node status in both cohorts. Moreover, in the stroma, SLI displayed a broad spectrum of inhibitory immune cells, by expressing several major immune checkpoint molecules, i.e. programmed cell death protein 1, programmed death-ligand 1, indoleamine 2,3-dioxygenase, and T-cell immunoglobulin and mucin domain 3. CONCLUSION: Intense pre-existing SLI was validated as a reliable marker of poorer prognosis for survival in UCB patients, which may add to the prognostic significance of the TNM classification.