Response of high-risk of recurrence/progression bladder tumours expressing sialyl-Tn and sialyl-6-T to BCG immunotherapy.
BACKGROUND
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
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.
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D000368:Aged; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis* / Q000276:immunology; D001500:BCG Vaccine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000096:biosynthesis* / Q000276:immunology; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000473:pathology; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000473:pathology / Q000601:surgery / Q000628:therapy*
D015295:Antigens, Tumor-Associated, Carbohydrate; D001500:BCG Vaccine; D014408:Biomarkers, Tumor; D009077:Mucins; C087769:sialosyl-T antigen; C055491:sialosyl-Tn antigen