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
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.
J Clin Invest. 2017 Aug 1;127(8):2916-2929. doi: 10.1172/JCI89717. Epub 2017 Jun 26.
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.
非肌层浸润性膀胱癌（NMIBC）是一种具有高度复发性的肿瘤，尽管采用卡介苗（BCG）疫苗进行膀胱内免疫治疗灌注。在一项前瞻性纵向研究中，我们利用BCG灌注增加局部免疫浸润的特点，将NMIBC患者尿液中的免疫细胞群作为膀胱肿瘤微环境的替代物进行特征分析。我们观察到中性粒细胞、T细胞、单核细胞来源的髓系抑制细胞（M-MDSC）和2型固有淋巴细胞（ILC2）的浸润。值得注意的是，T细胞与MDSC比值小于1的患者无复发生存率显著低于比值大于1的患者。对早期和晚期时间点的分析表明，这种患者二分法在BCG治疗之前就已存在。ILC2频率与尿液中可检测到的IL-13相关，并与募集的M-MDSC水平相关，M-MDSC高表达IL-13受体α1。在体外，在BCG或肿瘤细胞存在的情况下，ILC2增加并强力表达IL-13。IL-13诱导单核细胞的优先募集和抑制功能。因此，与偏向2型免疫相关的T细胞与MDSC平衡可能预测膀胱肿瘤复发并影响肌层浸润性癌患者的死亡率。此外，这些结果强调了ILC2/IL-13轴作为一种可靶向的途径，以减少M-MDSC区室并改善膀胱癌治疗。
