ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence
ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence
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DOI：
10.1172/jci89717
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发表时间：
2017-08-01
影响因子：
15.9
通讯作者：
Derre, Laurent
中科院分区：
文献类型：
--
作者：
Chevalier, Mathieu F.;Trabanelli, Sara;Derre, Laurent
尽管使用卡介苗（BCG）疫苗进行膀胱内免疫治疗，但非肌层浸润性膀胱癌（NMIBC）仍是一种高度复发的肿瘤。在一项前瞻性纵向研究中，我们利用可增加局部免疫浸润的卡介苗滴注来表征 NMIBC 患者尿液中的免疫细胞群，作为膀胱肿瘤微环境的替代。我们观察到中性粒细胞、T 细胞、单核细胞骨髓源性抑制细胞 (M-MDSC) 和第 2 组先天淋巴细胞 (ILC2) 的浸润。值得注意的是，T 细胞与 MDSC 比率小于 1 的患者的无复发生存率显着低于比率大于 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 治疗之前就存在。 ILC2 频率与尿液中可检测到的 IL-13 相关，并与招募的 M-MDSC 水平相关，M-MDSC 高度表达 IL-13 受体 α1。在体外，在 BCG 或肿瘤细胞存在的情况下，ILC2 增加并有效表达 IL-13。 IL-13 诱导单核细胞的优先募集和抑制功能。因此，T 细胞与 MDSC 的平衡与 2 型免疫的偏向相关，可以预测膀胱肿瘤复发并影响肌肉浸润性癌症患者的死亡率。此外，这些结果强调了 ILC2/IL-13 轴作为减少 M-MDSC 区室和改善膀胱癌治疗的靶向途径。
Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guerin (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 alpha 1. 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.