T regulatory type 1 cells in squamous cell carcinoma of the head and neck: Mechanisms of suppression and expansion in advanced disease
T regulatory type 1 cells in squamous cell carcinoma of the head and neck: Mechanisms of suppression and expansion in advanced disease
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DOI：
10.1158/1078-0432.ccr-07-5126
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发表时间：
2008-06-15
影响因子：
11.5
通讯作者：
Whiteside, Theresa L.
中科院分区：
文献类型：
--
作者：
Bergmann, Christoph;Strauss, Laura;Whiteside, Theresa L.
目的：调节性T细胞在肿瘤逃避免疫监视中起重要作用。调节性T细胞1型（Tr 1）是存在于头颈部鳞状细胞癌（HNSCC）患者的肿瘤和外周循环中的调节性T细胞的一个亚群，介导免疫抑制并可能促进肿瘤进展。从外周血单个核细胞（PBMC）或肿瘤浸润淋巴细胞（TIL）中分离CD 4（+）CD 25（-）T细胞，26例HNSCC患者和10例正常对照。在存在白细胞介素（IL）-2，IL-10和IL-15（各为10 - 20 IU/mL）的情况下，在培养前后测定Tr 1细胞表型。在Transwell系统中，使用或不使用中和抗IL-10或抗转化生长因子-β（1）（TGF-β（1））单克隆抗体，在基于羧基荧光素二乙酸琥珀酰亚胺酯的增殖测定中测量抑制。结果：T0细胞来源于HNSCC患者外周血单个核细胞（PBMC）和TIL中的CD 4（+）CD 25（-）前体细胞。细胞因子驱动的TO前体的离体扩增产生了CD 4（+）CD 25（-）Foxp 3（低）CD 132（+）IL-10（+）TGF-β（+）（1）群体，其介导比正常对照的TO细胞更高的抑制（P < 0.0001）。Tr 1细胞通过分泌IL-10和TGF-β 1抑制自体应答者的增殖。TIL来源的TO细胞中这些细胞因子的表达高于PBMC来源的TO细胞（P < 0.0001）。Tr 1细胞的频率和抑制功能显着较高的患者提出先进的比早期的疾病阶段，并在患者“治愈”的肿瘤治疗比那些活动性diseases.Conclusions：在HNSCC，Tr 1细胞生成促进在肿瘤部位。Tr 1细胞使用TGF-β和IL-10介导抑制。它们在疾病进展期间以及在没有明显疾病的患者中进行癌症治疗后扩展。
Purpose: 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.Experimental Design: 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-beta(1) (TGF-beta(1)) monoclonal antibodies in Transwell systems. ELISA was used to define the Tr1 cytokine profile.Results: TO cells originate from CD4(+)CD25(-) precursors present in TIL and PBMC of HNSCC patients. Cytokine-driven ex vivo expansion of TO precursors yielded CD4(+)CD25(-)Foxp3(low)CD 132(+)IL-10(+)TGF-beta(+)(1) populations that mediated higher suppression than TO cells of normal controls (P < 0.0001). Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-beta(1) secretion. Expression of these cytokines was higher in TIL-derived than PBMC-derived TO 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.Conclusions: 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.