Pichler Renate, Gruenbacher Georg, Culig Zoran, Brunner Andrea, Fuchs Dietmar, Fritz Josef, Gander Hubert, Rahm Andrea, Thurnher Martin
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.
Cancer Immunol Immunother. 2017 Apr;66(4):427-440. doi: 10.1007/s00262-016-1945-z. Epub 2016 Dec 22.
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.
尽管最近有报道称卡介苗（BCG）应答者存在Th2倾向，但Th1型免疫被认为是膀胱癌对BCG产生有效反应所必需的。本研究旨在评估23例接受BCG治疗患者中Th1和Th2成分之间的关系。前瞻性收集患者在基线期、BCG治疗期间及治疗后的外周血、血清和尿液样本。检测Th1（新蝶呤、色氨酸、犬尿氨酸、犬尿氨酸与色氨酸比值（KTR）、IL-12、IFN-γ、可溶性TNF-R75和IL-2Rα）和Th2（IL-4、IL-10）生物标志物以及辅助性T细胞（Th）、效应性T细胞和调节性T细胞中的CD4表达。通过免疫组织化学检测福尔马林固定、石蜡包埋的癌组织中的局部免疫细胞亚群，以检查控制Th1型（T-bet）和Th2型（GATA3）免疫的转录因子的表达。我们证实了存在Th2倾向，平均GATA3/T-bet比值为5.51。BCG应答者在治疗期间尿（p = 0.003）和血清新蝶呤（p = 0.012）、犬尿氨酸（p = 0.015）、KTR（p = 0.005）、IFN-γ（p = 0.005）和IL-12（p = 0.003）水平显著升高，而与无应答者相比，IL-10水平显著降低（p < 0.001）。首次BCG灌注后，GATA3/T-bet比值与血清新蝶呤（p = 0.008）、IFN-γ（p = 0.013）和KTR（p = 0.018）呈正相关。我们观察到Th细胞群体中CD4表达显著增加（p < 0.05），与无应答者相比，应答者中频率仅略有升高趋势（p = 0.303）。GATA3/T-bet比值、新蝶呤和KTR的联合评估可能是预测BCG应答的有用生物标志物。诸如GATA3等促进Th2的因子可能触发Th1型免疫反应，从而有助于BCG治疗成功。
