Prediction of non-muscle-invasive bladder cancer recurrence by measurement of checkpoint HLAG’s receptor ILT2 on peripheral CD8+ T cells

Francois Desgrandchamps,Nathalie Rouas-Freiss,Alexandra Masson-Lecomte,Stephane Culine,Jerome Verine,Clement Dumont,Amory De Gouvello,Annabelle Goujon,Ching-Lien Wu,Edgardo D Carosella,Christophe Hennequin,Joel Lemaoult,Adrien Riviere,Malika Djouadou,Antonio Rivero-Juarez

doi:10.18632/oncotarget.26036

Abstract

Background and ObjectiveRecurrence of non-muscle invasive bladder cancer (NMIBC) after initial management occurs in 60–70% of patients. Predictive criteria for recurrence remain only clinical and pathological. The aim of this study was to investigate the prognostic significance of the proportion of checkpoint HLA-G’s receptor ILT2-expressing peripheral CD8+ T cells.ResultsThe proportion of CD4+ILT2+and CD8+ILT2+ T cells was not increased in NMIBC compared to controls. However, a strong association was found between recurrence and CD8+ILT2+ T cell population levels (p = 0.0006). Two-year recurrence-free survival was 83% in patients with less than 18% CD8+ILT2+ T cells, 39% in the intermediary group, and 12% in patients with more than 46% CD8+ILT2+ T cells. Multivariate analyses demonstrated that the proportion of CD8+ILT2+ T cells was an independent predictive factor for recurrence. Adding CD8+ILT2+ T cells population level to clinical variables increased the predictive accuracy of the model by 4.5%.Materials and MethodsAll patients treated for NMIBC between 2012 and 2014 were included prospectively. Blood samples, tumor and clinico-pathological characteristics were collected. HLA-G expression was measured using IHC, and CD8+ILT2+ T cell levels using flow cytometry. Association between HLA-G and CD8+ILT2+ T cell population levels with NMIBC risk of recurrence was investigated using Cox regression analyses. Prediction was measured using the concordance index statistic.ConclusionsWe demonstrated a strong association between the proportion of circulating CD8+ILT2+ T cells and NMIBC risk of recurrence. Gain in prediction was substantial. If externally validated, such immunological marker could be integrated to predict NMIBC recurrence.

Highlights

Bladder cancer is the second most common genitourinary tract malignancy worldwide [1]. 75% to 85% of patients are initially diagnosed with non-muscle invasive disease (NMIBC) [2]
We demonstrated a strong association between the proportion of circulating CD8+ILT2+ T cells and non-muscle invasive bladder cancer (NMIBC) risk of recurrence
HLA-G is an immune checkpoint molecule well known for its tolerogenic role in maternal-fetal tolerance, and that is commonly neo-expressed by solid tumors

Summary

Introduction

Bladder cancer is the second most common genitourinary tract malignancy worldwide [1]. 75% to 85% of patients are initially diagnosed with non-muscle invasive disease (NMIBC) [2]. To predict the short- and long-term probabilities of disease recurrence and progression, two different scoring systems and risk tables were developed [4,5,6] based on clinical and pathological parameters by the European Organization for Research and Treatment of Cancer (EORTC) and by the Spanish Urological Club for Oncological Treatment (CUETO). The inhibition of immune checkpoints (in particular PD1/PD-L1 and CTLA4) is a promising therapeutic approach for the management of cancer It has already been approved in some cancers, and is being evaluated in the context of genitourinary cancers including bladder [13]. The aim of this study was to investigate the prognostic significance of the proportion of checkpoint HLA-G’s receptor ILT2expressing peripheral CD8+ T cells

Objectives

Methods

Results

Discussion

Conclusion