Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer

Renate Pichler,Dietmar Fuchs,Martin Thurnher,Georg Gruenbacher,Hubert Gander,Zoran Culig,Josef Fritz,Andrea Rahm,Andrea Brunner

doi:10.1007/s00262-016-1945-z

Renate Pichler, Dietmar Fuchs + Show 7 more

Open Access

https://doi.org/10.1007/s00262-016-1945-z

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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.

Highlights

After decades of skepticism, immunotherapy is poised to become a mainstay of cancer treatment [1]
Treatment with Bacillus Calmette–Guérin (BCG) belongs to the most successful cancer immunotherapies, and in high-risk, non-muscle-invasive bladder cancer (NMIBC), it is the standard adjuvant treatment according to the European Association of Urology (EAU) guidelines [4]
Histopathological evaluation confirmed a primary, high-risk NMIBC according to the European Organization for Research and Treatment of Cancer (EORTC) scoring system and risk tables [37]

Summary

Introduction

Immunotherapy is poised to become a mainstay of cancer treatment [1]. It is well established that innate lymphocytes including NK cells participate in the early innate response and promote and shape the subsequent adaptive response by triggering dendritic cell maturation [8] and are essential for effective BCG immunotherapy [9, 10]. Different cytokines such as interleukin (IL)-1, IL-2, IL-6, IL-7, IL-8, IL-10, IL-12, tumor necrosis factor-(TNF)-α and interferon (IFN)-γ are released and can be detected in patients treated with BCG [11,12,13]. Significant increases in urine concentrations of Th1-type cytokines during treatment were noticed in BCG responders [21, 22]

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