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J Clin Invest. 2017 Aug 1;127(8):2916-2929. doi: 10.1172/JCI89717. Epub 2017 Jun 26.

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

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Urology Research Unit, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
Translational Tumor Immunology, Ludwig Center for Cancer Research at the University of Lausanne, Department of Fundamental Oncology, Epalinges, Switzerland.
Computational Cancer Biology, Ludwig Center for Cancer Research at the University of Lausanne, Epalinges, Switzerland.
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
Department of Oncology and Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland.
Department of Urology, University Hospital of Basel, Basel, Switzerland.


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.

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