Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses
Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses
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瘤内产生 IL22 的细胞定义了免疫逃避亚型肌肉浸润性膀胱癌，其预后不良，但纳武单抗反应优异
DOI：
10.1002/ijc.32715
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发表时间：
2019
影响因子：
6.4
通讯作者：
Xu Jiejie
中科院分区：
文献类型：
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作者：
Zeng Han;Liu Zheng;Wang Zewei;Zhou Quan;Qi Yangyang;Chen Yifan;Chen Lingli;Zhang Peipei;Wang Jiajun;Chang Yuan;Bai Qi;Xia Yu;Wang Yiwei;Liu Li;Zhu Yu;Dai Bo;Guo Jianming;Xu Le;Zhang Weijuan;Xu Jiejie
我们以前的研究已经发现了免疫逃逸亚型肌肉浸润性膀胱癌(MIBC)，其特征是免疫细胞浸润模式。本研究探讨MIBC瘤内产生IL22细胞的临床意义、免疫调节作用及治疗价值。对259例福尔马林固定石蜡包埋标本和83例新鲜切除标本和391例TCGA标本进行了回顾性分析。免疫组织化学和流式细胞术检测免疫细胞的浸润和功能状态，体外干预实验检测IL22+细胞的治疗和预测能力。我们的数据显示，在训练和验证队列中，IL22+细胞浸润率高的患者总体存活率和无复发存活率都很低。仅IL22+细胞浸润率低的联合队列pt2患者从辅助化疗(ACT)中获得明显的生存益处。此外，在IL22+细胞密度高的患者中，免疫环境以促肿瘤细胞和免疫抑制细胞因子增加为特征。高IL22+T细胞亚群CD8+T细胞耗竭和效应标志的表达模式提示其功能紊乱。重要的是，nivolumab在高IL22+细胞浸润的肿瘤中显示出杀瘤效果，而在抗IL22抗体治疗的肿瘤中，CD8+T细胞耗尽的免疫抑制环境被取消。综上所述，IL22+细胞的渗透决定了CD8+T细胞功能障碍的免疫抑制状态。肿瘤浸润性IL22+细胞可作为预测预后和ACT疗效的独立标志物。IL22+细胞的浸润有可能成为尼伏单抗应用的良好预测指标，阻断IL22有可能成为治疗MIBC的新策略。
Our previous researches have identified immunoevasive subtype muscle‐invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22‐producing cells in MIBC. Two hundred and fifty‐nine formalin‐fixed paraffin‐embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status.In vitrointervention studies were to test the therapeutic and predictive potential of IL22+cells. Our data revealed patients with high IL22+cells infiltration suffered poor overall survival and recurrence‐free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro‐tumor cells and immunosuppressive cytokines was identified in patients with high IL22+cells density. The expression pattern of exhausted and effector markers in CD8+T cells from high IL22+cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor‐killing efficacy in tumors with high IL22+cells infiltration, and immunosuppressive contexture with CD8+T cells exhaustion was abrogated in tumors treated with anti‐IL22 antibody. In summary, IL22+cells infiltration determined immunosuppressive contexture with CD8+T cell dysfunction. Tumor‐infiltrating IL22+cells could be used as an independent marker to predict prognosis and ACT responses. IL22+cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.