Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

Abstract

// Renate Pichler 1 , Josef Fritz 2 , Claudia Zavadil 3 , Georg Schäfer 3 , Zoran Culig 1 , Andrea Brunner 3 1 Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria 2 Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, A-6020 Innsbruck, Austria 3 Department of Pathology, Division of General Pathology, Medical University of Innsbruck, A-6020 Innsbruck, Austria Correspondence to: Andrea Brunner, email: Andrea.Brunner@i-med.ac.at Keywords: lymphocytes, tumor-associated macrophages, BCG immunotherapy, bladder cancer, tumor microenvironment Received: March 22, 2016      Accepted: May 05, 2016      Published: May 21, 2016 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.