title: Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer.
abstract: Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-γ (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p < 0.001) compared to non-responders. GATA3/T-bet ratio correlated positively with serum neopterin (p = 0.008), IFN-γ (p = 0.013) and KTR (p = 0.018) after the first BCG instillation. We observed a significant increase in CD4 expression in the Th cell population (p < 0.05), with only a modest tendency toward higher frequency in responders compared to non-responders (p = 0.303). The combined assessment of GATA3/T-bet ratio, neopterin and KTR may be a useful biomarker in predicting BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success.
authors.affiliation: Department of Urology, Research Group of Urologic Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. Renate.Pichler@i-med.ac.at.
authors.forename: Renate
authors.initials: R
authors.lastname: Pichler
authors.affiliation: Department of Urology, Research Group of Urologic Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.|Immunotherapy Research Unit, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Gruenbacher
authors.affiliation: Department of Urology, Research Group of Urologic Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.|Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.affiliation: Division of General Pathology, Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brunner
authors.affiliation: Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Fritz
authors.affiliation: Department of Urology, Research Group of Urologic Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.|Immunotherapy Research Unit, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gander
authors.affiliation: Department of Urology, Research Group of Urologic Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.|Immunotherapy Research Unit, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rahm
authors.affiliation: Department of Urology, Research Group of Urologic Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.|Immunotherapy Research Unit, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Thurnher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000276:immunology*; D019798:Neopterin / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000628:therapy*; D000098815:T-bet Transcription Factor
chemical_list: D015415:Biomarkers; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D019798:Neopterin
keywords: BCG; Bladder cancer; GATA3; Neopterin; T cells; T-bet