Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS: Data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer.

Alexander C Dowell,Graham S Taylor,Vinnie During,Richard T Bryan,Ellen Cobby,Maurice P Zeegers,Kar K Cheng,Kaisheng Wen,Jane Anderson,Nicholas D James,Adam J Devall

doi:10.1371/journal.pone.0184841

Abstract

The tumour immune microenvironment is considered to influence cancer behaviour and outcome. Using a panel of markers for innate and adaptive immune cells we set out to characterise and understand the bladder tumour microenvironment of 114 patients from a prospective multicentre cohort of newly-diagnosed bladder cancer patients, followed-up for 4.33±1.71 years. We found IL-17-positive cells were significantly increased in primary and concomitant carcinoma in situ (CIS), p<0.0001, a highly malignant lesion which is the most significant single risk factor for disease progression. Further characterisation of the tumour immunophenotype identified IL-17+ cells as predominantly mast cells rather than T-cells, in contrast to most other tumour types. Expression of the IL-17-receptor in bladder tumours, and functional effects and gene expression changes induced by IL-17 in bladder tumour cells in vitro suggest a role in tumour behaviour. Finally, we assessed the effects of IL-17 in the context of patient outcome, following intravesical BCG immunotherapy which is the standard of care; higher numbers of IL-17+ cells were associated with improved event-free survival (p = 0.0449, HR 0.2918, 95% CI 0.08762–0.9721) in patients with primary and concomitant CIS (n = 41), we propose a model of IL-17+ Mast cells mechanism of action. Thus, in the context of bladder CIS, IL-17+ mast cells predict favourable outcome following BCG immunotherapy indicative of a novel mechanism of BCG immunotherapy in UBC and could form the basis of a stratified approach to treatment.

Highlights

Bladder cancer is the seventh most common cancer in Western society, with a global incidence of over 380,000 [1,2]
The most significant single risk factor for progression to muscle-invasive bladder cancer (MIBC) is the presence of primary or concomitant carcinoma in situ (CIS) [8]. This flat high-grade dysplasia is highly malignant with significant potential for invasion; patients diagnosed with CIS undergo additional treatments following TURBT, principally repeated cycles of intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in a regimen of induction and maintenance [9]
The most novel finding was the marked variation in the numbers of IL-17+ cells between different patients’ tumours, with increased numbers of these cells significantly associated with CIS

Summary

Introduction

Bladder cancer is the seventh most common cancer in Western society, with a global incidence of over 380,000 [1,2]. The most significant single risk factor for progression to MIBC is the presence of primary or concomitant carcinoma in situ (CIS) [8] This flat high-grade dysplasia is highly malignant with significant potential for invasion; patients diagnosed with CIS undergo additional treatments following TURBT, principally repeated cycles of intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in a regimen of induction and maintenance [9]. Despite these efforts, 50% of patients relapse and are at high risk of progression to MIBC, with poor prognosis [10]. There are currently no prognostic markers to identify those CIS patients who will respond to therapy and those who will relapse [9]

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