ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence
Mathieu F. Chevalier, … , Camilla Jandus, Laurent Derré
Mathieu F. Chevalier, … , Camilla Jandus, Laurent Derré
Published June 26, 2017
Citation Information: J Clin Invest. 2017;127(8):2916-2929. https://doi.org/10.1172/JCI89717.
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Research Article Immunology Oncology

ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence

Abstract

Non-muscle–invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell–to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell–to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment.

Authors

Mathieu F. Chevalier, Sara Trabanelli, Julien Racle, Bérengère Salomé, Valérie Cesson, Dalila Gharbi, Perrine Bohner, Sonia Domingos-Pereira, Florence Dartiguenave, Anne-Sophie Fritschi, Daniel E. Speiser, Cyrill A. Rentsch, David Gfeller, Patrice Jichlinski, Denise Nardelli-Haefliger, Camilla Jandus, Laurent Derré

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Figure 5

IL-13 is produced by ILC2 upon BCG stimulation and is able to recruit and induce suppressive function in monocytic cells.

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IL-13 is produced by ILC2 upon BCG stimulation and is able to recruit an...
(A) Frequencies of ILC2 in urine samples with undetectable (n = 7) versus detectable (n = 6) urinary IL-13 (detection limit: 5 pg/ml). (B) Representative FACS histograms of IL-13–producing ILC2 upon stimulation with BCG (MOI = 1) or medium alone in PBMCs from HDs (n = 6) and MIBC patients (n = 5) and (C) their quantification. (D) IL-13 production in ILC2 from patients with MIBC following coculture with nonmalignant urothelium (HCV-29), Bu68.8, or TCC-Sup tumor cell lines. (C and D) Statistical analysis was performed using a 2-tailed, paired Student’s t test to compare stimulated versus medium-only conditions and a 2-tailed, unpaired Student’s t test to compare patients with HDs (C) and 1-way ANOVA followed by Dunnett’s test to compare cell lines with the control condition (D). (E) Representative example of IL-13Rα1 labeling. (F) Levels of ex vivo IL-13Rα1 expression on the indicated monocytic cells from PBMCs obtained from HDs (n = 9), NMIBC patients (n = 18), and MIBC patients (n = 10) and from post-BCG urine samples (n = 8), expressed as the ratio of mean fluorescence intensity (RFI) of specific staining versus the isotype Ig control. A 2-tailed, paired Student’s t test was performed to compare M-MDSCs with CD14+HLA-DR+/hi cells and an unpaired Student’s t test to compare urine with circulating counterparts. (G) Chemotactic response of CD14+ cells and CD3+/CD19+ lymphocytes from HD PBMCs (n = 6; upper chamber) to medium alone or IL-13 (100 ng/ml; lower chamber) using Transwell plates. (H) Representative FACS histograms of CFSE-labeled activated T cells cultured alone or with purified CD14+ cells pretreated with IL-13 (IL-13–treated CD14+ cells) or not (CD14+ cells). (I and J) Quantification of the proliferation index in CD8+ (I) and CD4+ (J) T cells. (K) IL-13 concentration in supernatants of PBMCs (n = 8) subjected to 3 days of stimulation with BCG or no stimulation. (L) Representative example of CFSE-labeled activated CD8+ T cells cocultured with CD14+ cells previously conditioned with filtered supernatants of unstimulated or BCG-stimulated PBMCs in the presence of either anti–IL-13–blocking antibody or isotype IgG1 control (10 μg/ml each). (M) Comparison of the proliferation index in each indicated condition (n = 3, representative of 2 independent sets of experiments). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-tailed, paired Student’s t test (G–K) and 1-way ANOVA followed by Tukey’s test (M). Div, percentage of cells with at least 1 division; Ig, isotype IgG1 control; PI, proliferation index; SN, supernatant.