Bergmann Christoph, Strauss Laura, Wang Yun, Szczepanski Miroslaw J, Lang Stephan, Johnson Jonas T, Whiteside Theresa L
Departments of Pathology and Biostatistics, University of Pittsburgh Cancer Institute, Pittsburg, Pennsylvania, USA.
Clin Cancer Res. 2008 Jun 15;14(12):3706-15. doi: 10.1158/1078-0432.CCR-07-5126.
Regulatory T cells play a major role in tumor escape from immunosurveillance. T regulatory cells type 1 (Tr1), a subset of regulatory T cells present in the tumor and peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC), mediate immune suppression and might contribute to tumor progression.
CD4+CD25-T cells were isolated from peripheral blood mononuclear cells (PBMC) or tumor-infiltrating lymphocytes (TIL) of 26 HNSCC patients and 10 normal controls. The Tr1 cell phenotype was determined before and after culture in the presence of interleukin (IL)-2, IL-10, and IL-15, each at 10 to 20 IU/mL. Suppression was measured in carboxyfluorescein diacetate succinimidyl ester-based proliferation assays with or without neutralizing anti-IL-10 or anti-transforming growth factor-beta1 (TGF-beta1) monoclonal antibodies in Transwell systems. ELISA was used to define the Tr1 cytokine profile.
Tr1 cells originate from CD4(+)CD25(-) precursors present in TIL and PBMC of HNSCC patients. Cytokine-driven ex vivo expansion of Tr1 precursors yielded CD4+CD25-Foxp3lowCD132+IL-10+TGF-beta1+ populations that mediated higher suppression than Tr1 cells of normal controls (P < 0.0001). Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-beta1 secretion. Expression of these cytokines was higher in TIL-derived than PBMC-derived Tr1 cells (P < 0.0001). The Tr1 cell frequency and suppressor function were significantly higher in patients presenting with advanced than early disease stages and in patients "cured" by oncologic therapies than in those with active disease.
In HNSCC, Tr1 cell generation is promoted at the tumor site. Tr1 cells use TGF-beta and IL-10 to mediate suppression. They expand during disease progression and also following cancer therapy in patients with no evident disease.
调节性T细胞在肿瘤逃避免疫监视中起主要作用。1型调节性T细胞（Tr1）是头颈部鳞状细胞癌（HNSCC）患者肿瘤及外周血循环中存在的调节性T细胞亚群，介导免疫抑制并可能促进肿瘤进展。
从26例HNSCC患者及10例正常对照的外周血单个核细胞（PBMC）或肿瘤浸润淋巴细胞（TIL）中分离出CD4+CD25-T细胞。在存在白细胞介素（IL）-2、IL-10和IL-15（各10至20 IU/mL）的情况下培养前后，确定Tr1细胞表型。在Transwell系统中，通过基于羧基荧光素二乙酸琥珀酰亚胺酯的增殖试验，在有或没有中和性抗IL-10或抗转化生长因子-β1（TGF-β1）单克隆抗体的情况下测量抑制作用。采用酶联免疫吸附测定（ELISA）来确定Tr1细胞因子谱。
Tr1细胞起源于HNSCC患者TIL和PBMC中存在的CD4(+)CD25(-)前体细胞。细胞因子驱动的Tr1前体细胞体外扩增产生了CD4+CD25-Foxp3lowCD132+IL-10+TGF-β1+群体，其介导的抑制作用高于正常对照的Tr1细胞（P < 0.0001）。Tr1细胞通过分泌IL-10和TGF-β1抑制自体反应细胞的增殖。这些细胞因子在TIL来源的Tr1细胞中的表达高于PBMC来源的Tr1细胞（P < 0.0001）。晚期疾病患者的Tr1细胞频率和抑制功能显著高于早期疾病患者，接受肿瘤治疗“治愈”的患者高于患有活动性疾病的患者。
在HNSCC中，肿瘤部位促进了Tr1细胞的生成。Tr1细胞利用TGF-β和IL-10介导抑制作用。它们在疾病进展过程中以及在无明显疾病的患者接受癌症治疗后都会扩增。
