Elevated pre-existing lymphocytic infiltrates in tumour stroma predict 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.