Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University.
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University.
Histopathology. 2019 Sep;75(3):354-364. doi: 10.1111/his.13807. Epub 2019 Jul 2.
Lymphocytic infiltrates are predominantly distributed in the tumour stroma, and represents the tumour-related immune response. The aim of this study was to elucidate the prognostic value of stromal lymphocytic infiltrates (SLI) in resectable urothelial carcinoma of the bladder (UCB).
The prognostic significance of SLI in UCB was assessed in a discovery cohort (n = 226; 60 deaths) and in a validation cohort (n = 417; 103 deaths). SLI was categorised into intense (≥50% SLI) and non-intense (<50% SLI). A multivariable Cox model was used to analyse the associations of SLI score with overall survival (OS) and disease-free survival. Immunofluorescence staining was used to examine the composition and phenotypes of SLI. The median follow-up times were 58.1 and 64.9 months in the discovery and validation cohorts, respectively. SLI was intense in 38.1% of patients in the discovery cohort and in 20.9% of patients in the validation cohort (P < 0.001). SLI score had independent prognostic value for OS [hazard ratio (HR) 2.132; P = 0.016] and disease-specific survival (DSS) (HR 1.952; P = 0.04) in the discovery cohort, which was confirmed in the validation cohort (OS: HR 1.636; P = 0.023; DSS: HR 1.627; P = 0.029). SLI score was positively associated with histological grade, tumour stage and lymph node status in both cohorts. Moreover, in the stroma, SLI displayed a broad spectrum of inhibitory immune cells, by expressing several major immune checkpoint molecules, i.e. programmed cell death protein 1, programmed death-ligand 1, indoleamine 2,3-dioxygenase, and T-cell immunoglobulin and mucin domain 3.
Intense pre-existing SLI was validated as a reliable marker of poorer prognosis for survival in UCB patients, which may add to the prognostic significance of the TNM classification.
淋巴细胞浸润主要分布在肿瘤基质中，代表与肿瘤相关的免疫反应。本研究旨在阐明在可切除的膀胱癌（UCB）中基质淋巴细胞浸润（SLI）的预后价值。
在发现队列（n=226；60 例死亡）和验证队列（n=417；103 例死亡）中评估了 SLI 在 UCB 中的预后意义。将 SLI 分为强（≥50% SLI）和非强（<50% SLI）。多变量 Cox 模型用于分析 SLI 评分与总生存（OS）和无病生存（DFS）的相关性。免疫荧光染色用于检查 SLI 的组成和表型。发现队列和验证队列的中位随访时间分别为 58.1 个月和 64.9 个月。在发现队列中，38.1%的患者 SLI 较强，而在验证队列中，20.9%的患者 SLI 较强（P<0.001）。SLI 评分对 OS [风险比（HR）2.132；P=0.016]和发现队列中疾病特异性生存（DSS）（HR 1.952；P=0.04）具有独立的预后价值，在验证队列中得到了证实（OS：HR 1.636；P=0.023；DSS：HR 1.627；P=0.029）。在两个队列中，SLI 评分与组织学分级、肿瘤分期和淋巴结状态均呈正相关。此外，在基质中，SLI 通过表达几种主要的免疫检查点分子，即程序性细胞死亡蛋白 1、程序性死亡配体 1、吲哚胺 2,3-双加氧酶和 T 细胞免疫球蛋白和粘蛋白结构域 3，显示出广泛的抑制性免疫细胞谱。
强烈的预先存在的 SLI 被验证为 UCB 患者生存预后较差的可靠标志物，这可能增加了 TNM 分类的预后意义。
