title: Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer.
abstract: Although Bacillus Calmette-Guérin (BCG) is the most successful immunotherapy for high-risk non-muscle-invasive bladder cancer, approximately 30% of patients are unresponsive to treatment. New biomarkers are important to identify patients who will benefit most from BCG during a worldwide BCG shortage. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded tissue sections of bladder cancer by immunohistochemistry, using monoclonal antibodies to tumor-associated macrophages (TAMs; CD68, CD163), B-lymphocytes (CD20) and T-lymphocyte subsets (CD3, CD4, CD8, GATA3, T-bet, FOXP3 and CD25). Cell densities in the lamina propria without invasion, at the invasive front if present, in the papillary tumor stroma, and in the neoplastic urothelium were calculated. Twenty-nine (72.5%) of 40 patients were classified as BCG responders after a mean follow-up of 35.3 months. A statistically significant association was observed for BCG failure with low density of CD4+ and GATA3+ T-cells, and increased expression of FOXP3+ and CD25+ regulatory T-cells (Tregs) as well as CD68+ and CD163+ TAMs. Survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with an increased count of CD4+ and GATA3+ T-cells. TAMs, Tregs and T-bet+ T-cells were inversely correlated with RFS. Thus, the tumor microenvironment seems to influence the therapeutic response to BCG, permitting an individualized treatment.
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Pichler
authors.affiliation: Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Fritz
authors.affiliation: Department of Pathology, Division of General Pathology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Zavadil
authors.affiliation: Department of Pathology, Division of General Pathology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.affiliation: Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.affiliation: Department of Pathology, Division of General Pathology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brunner
mesh_terms: D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D001500:BCG Vaccine / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D010865:Pilot Projects; D016016:Proportional Hazards Models; D018418:Th2 Cells / Q000166:cytology; D059016:Tumor Microenvironment; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001500:BCG Vaccine; D014408:Biomarkers, Tumor
keywords: BCG immunotherapy; bladder cancer; lymphocytes; tumor microenvironment; tumor-associated macrophages