1] Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal [2] Institute of Biomedical Sciences of Abel Salazar, University of Porto, Porto, Portugal [3] Nucleo de Investigação em Farmácia-Centro de Investigação em Saúde e Ambiente (CISA), Health School of the Polytechnic Institute of Porto, Porto, Portugal [4] LPCC, Research Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal.
Br J Cancer. 2013 Oct 15;109(8):2106-14. doi: 10.1038/bjc.2013.571. Epub 2013 Sep 24.
High risk of recurrence/progression bladder tumours is treated with Bacillus Calmette-Guérin (BCG) immunotherapy after complete resection of the tumour. Approximately 75% of these tumours express the uncommon carbohydrate antigen sialyl-Tn (Tn), a surrogate biomarker of tumour aggressiveness. Such changes in the glycosylation of cell-surface proteins influence tumour microenvironment and immune responses that may modulate treatment outcome and the course of disease. The aim of this work is to determine the efficiency of BCG immunotherapy against tumours expressing sTn and sTn-related antigen sialyl-6-T (s6T).
In a retrospective design, 94 tumours from patients treated with BCG were screened for sTn and s6T expression. In vitro studies were conducted to determine the interaction of BCG with high-grade bladder cancer cell line overexpressing sTn.
From the 94 cases evaluated, 36 had recurrence after BCG treatment (38.3%). Treatment outcome was influenced by age over 65 years (HR=2.668; (1.344-5.254); P=0.005), maintenance schedule (HR=0.480; (0.246-0.936); P=0.031) and multifocality (HR=2.065; (1.033-4.126); P=0.040). sTn or s6T expression was associated with BCG response (P=0.024; P<0.0001) and with increased recurrence-free survival (P=0.001). Multivariate analyses showed that sTn and/or s6T were independent predictive markers of recurrence after BCG immunotherapy (HR=0.296; (0.148-0.594); P=0.001). In vitro studies demonstrated higher adhesion and internalisation of the bacillus to cells expressing sTn, promoting cell death.
s6T is described for the first time in bladder tumours. Our data strongly suggest that BCG immunotherapy is efficient against sTn- and s6T-positive tumours. Furthermore, sTn and s6T expression are independent predictive markers of BCG treatment response and may be useful in the identification of patients who could benefit more from this immunotherapy.
高复发/进展风险的膀胱癌在肿瘤完全切除后，采用卡介苗（BCG）免疫疗法进行治疗。这些肿瘤中约有 75%表达罕见的碳水化合物抗原唾液酸-Tn（Tn），它是肿瘤侵袭性的替代生物标志物。细胞表面蛋白糖基化的这种变化会影响肿瘤微环境和免疫反应，从而可能调节治疗效果和疾病进程。本研究旨在确定卡介苗免疫疗法对表达 sTn 和相关抗原唾液酸-6-T（s6T）的肿瘤的疗效。
在回顾性设计中，对 94 例接受 BCG 治疗的患者的肿瘤进行了 sTn 和 s6T 表达的筛查。进行了体外研究以确定 BCG 与高等级膀胱癌细胞系过度表达 sTn 的相互作用。
在 94 例评估病例中，36 例在 BCG 治疗后复发（38.3%）。治疗结果受年龄超过 65 岁（HR=2.668；（1.344-5.254）；P=0.005）、维持方案（HR=0.480；（0.246-0.936）；P=0.031）和多发性（HR=2.065；（1.033-4.126）；P=0.040）的影响。sTn 或 s6T 的表达与 BCG 反应相关（P=0.024；P<0.0001），并与无复发生存率的提高相关（P=0.001）。多变量分析表明，sTn 和/或 s6T 是 BCG 免疫治疗后复发的独立预测标志物（HR=0.296；（0.148-0.594）；P=0.001）。体外研究表明，表达 sTn 的细胞对细菌的黏附和内化作用增强，促进了细胞死亡。
s6T 首次在膀胱癌中描述。我们的数据强烈表明，BCG 免疫疗法对 sTn-和 s6T-阳性肿瘤有效。此外，sTn 和 s6T 的表达是 BCG 治疗反应的独立预测标志物，可用于识别可能从这种免疫疗法中获益更多的患者。
