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

• Published in: The Journal of clinical investigation Vol. 127; no. 8; pp. 2916 - 2929
• Main Authors: Chevalier, Mathieu F, Trabanelli, Sara, Racle, Julien, Salomé, Bérengère, Cesson, Valérie, Gharbi, Dalila, Bohner, Perrine, Domingos-Pereira, Sonia, Dartiguenave, Florence, Fritschi, Anne-Sophie, Speiser, Daniel E, Rentsch, Cyrill A, Gfeller, David, Jichlinski, Patrice, Nardelli-Haefliger, Denise, Jandus, Camilla, Derré, Laurent
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-08-2017
• Subjects: Administration, Intravesical; Aged; Aged, 80 and over; Analysis; Antigens; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine; Biomedical research; Bladder cancer; Cancer; Cellular signal transduction; Disease-Free Survival; Female; Gene expression; Genotype & phenotype; Humans; Immune System; Immunotherapy; Interleukin 13; Interleukin-13 - metabolism; Invasiveness; Leprosy; Leukocytes (neutrophilic); Longitudinal Studies; Lymphocytes; Lymphocytes - cytology; Lymphocytes T; Lymphoid cells; Male; Metastases; Middle Aged; Monocytes; Monocytes - cytology; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - urine; Neutrophils; Neutrophils - cytology; Patients; Prospective Studies; Recurrence (Disease); Rodents; Suppressor cells; Survival analysis; T cells; T-Lymphocytes - cytology; Tumor cells; Urinary bladder; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - therapy; Urinary Bladder Neoplasms - urine; Urine
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI89717

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.