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

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

doi:10.18632/oncotarget.26036

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

Oncotarget. 2018 Sep 4;9(69):33160-33169. doi: 10.18632/oncotarget.26036.

Authors

Francois Desgrandchamps^{1

2}, Joel LeMaoult^{1

3}, Annabelle Goujon^{1

2}, Adrien Riviere^{1

2}, Antonio Rivero-Juarez^{1

4}, Malika Djouadou^{1

2}, Amory de Gouvello^{1

2}, Clement Dumont^{1

5}, Ching-Lien Wu^{1

3}, Stephane Culine^{1

5}, Jerome Verine^{1

6}, Nathalie Rouas-Freiss^{1

3}, Christophe Hennequin^{1

7}, Alexandra Masson-Lecomte^{1

2}, Edgardo D Carosella^{1

3}

Affiliations

¹ CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France.
² AP-HP, Saint-Louis Hospital, Department of Urology, Paris, France.
³ University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hématologie, Saint-Louis Hospital, Paris, France.
⁴ Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.
⁵ AP-HP, Saint-Louis Hospital, Department of Medical Oncology, Paris, France.
⁶ AP-HP, Saint-Louis Hospital, Department of Pathology, Paris, France.
⁷ AP-HP, Saint-Louis Hospital, Department of Radiotherapy, Paris, France.

Abstract

Background and objective: Recurrence 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.

Results: The 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 methods: All 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.

Conclusions: We 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.

Keywords: HLA-G; ILT2; bladder; cancer; immune checkpoint.