Liu Zheng, Zhu Yu, Xu Le, Zhang Junyu, Xie Huyang, Fu Hangcheng, Zhou Quan, Chang Yuan, Dai Bo, Xu Jiejie
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Oncoimmunology. 2018 Aug 1;7(9):e1474317. doi: 10.1080/2162402X.2018.1474317. eCollection 2018.
Which subgroups patients with muscle-invasive bladder cancer (MIBC) could benefit most from adjuvant chemotherapy (ACT) is blurred. Here we tried to stratify MIBC patients with tumor infiltrating mast cells (TIMs), explore the prognostic and predictive value of TIMs, and provide possible cellular explanations. We selected 259 MIBC patients who underwent radical cystectomy from two independent clinical centers between 2002 and 2014. TIMs were evaluated and prognostic and predictive value was assessed. The CIBERSORT method, Gene Set Enrichment Analysis (GSEA) and differential gene expression analyses were performed to explore the possible cellular mechanisms. TIMs infiltration was distinct between stromal and epithelial area of MIBC specimens. Patients with higher stromal TIMs had a significant worse overall survival and recurrence free survival (HR = 2.228, 95%CI: 1.467-3.550; = 0.001 and HR = 1.984, 95%CI: 1.105-3.374; = 0.016). More importantly, pT2 patients with low stromal TIMs tended to have a lower risk of death and recurrence after ACT (HR = 0.233, 95%CI: 0.020-0.814; = 0.033 and HR = 0.180, 95%CI: 0.022-0.722; = 0.031). A negative correlativity between TIMs and CD8 + T cells was identified on TCGA-BLCA cohort. Immunohistochemistry results validated that high stromal TIMs were negatively correlated with CD8 + T cells (Spearman's rho = -0.215, < 0.001). Differential gene expression suggested that low TIMs might represent a state of immune activation in MIBC. To conclude, high stromal TIMs infiltration was an independent unfavorable prognosticator for MIBC patients. Patients with low stromal TIMs might benefit the most from ACT, especially in pT2 stage.
肌肉浸润性膀胱癌（MIBC）患者中哪些亚组能从辅助化疗（ACT）中获益最多仍不明确。在此，我们试图对伴有肿瘤浸润肥大细胞（TIMs）的MIBC患者进行分层，探究TIMs的预后和预测价值，并提供可能的细胞学解释。我们选取了2002年至2014年间来自两个独立临床中心的259例行根治性膀胱切除术的MIBC患者。对TIMs进行评估并分析其预后和预测价值。采用CIBERSORT方法、基因集富集分析（GSEA）和差异基因表达分析来探究可能的细胞机制。TIMs浸润在MIBC标本的基质和上皮区域有所不同。基质TIMs较高的患者总生存期和无复发生存期显著更差（HR = 2.228，95%CI：1.467 - 3.550；P = 0.001和HR = 1.984，95%CI：1.105 - 3.374；P = 0.016）。更重要的是，基质TIMs较低的pT2患者在接受ACT后死亡和复发风险往往较低（HR = 0.233，95%CI：0.020 - 0.814；P = 0.033和HR = 0.180，95%CI：0.022 - 0.722；P = 0.031）。在TCGA - BLCA队列中发现TIMs与CD8 + T细胞之间存在负相关性。免疫组化结果证实，基质TIMs高与CD8 + T细胞呈负相关（Spearman相关系数 = -0.215，P < 0.001）。差异基因表达提示低TIMs可能代表MIBC中的一种免疫激活状态。总之，基质TIMs高浸润是MIBC患者独立的不良预后因素。基质TIMs低的患者可能从ACT中获益最多，尤其是在pT2期。
