分泌白细胞介素-10和转化生长因子-β1的CD4+CD25高表达Foxp3+ T细胞的一个独特亚群介导肿瘤微环境中的抑制作用。

A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment.

作者信息

Strauss Laura, Bergmann Christoph, Szczepanski Miroslaw, Gooding William, Johnson Jonas T, Whiteside Theresa L

机构信息

University of Pittsburgh Cancer Institute, Pennsylvania 15213-1863, USA.

出版信息

Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4345-54. doi: 10.1158/1078-0432.CCR-07-0472.

DOI:10.1158/1078-0432.CCR-07-0472

PMID:17671115

Abstract

PURPOSE

Immunosuppression, including that mediated by CD4(+)CD25(high)Foxp3(+) regulatory T cells (Treg), is a characteristic feature of head and neck squamous cell carcinoma (HNSCC). Tregs with a distinct phenotype in tumor-infiltrating lymphocytes (TIL) contribute to local immune suppression.

EXPERIMENTAL DESIGN

The frequency and phenotype of Treg in TIL and/or peripheral blood mononuclear cells (PBMC) in 15 HNSCC patients and PBMC in 15 normal controls were compared. Single-cell sorted CD4(+)CD25(high) T cells were tested for regulatory function by coculture with carboxyfluorescein diacetate succinimidyl ester-labeled and activated autologous CD4(+)CD25(-) responder T cells. Transwell inserts separating Treg from responders and neutralizing interleukin-10 (IL-10) or transforming growth factor-beta1 (TGF-beta1) antibodies were used to evaluate the mechanisms used by Treg to suppress responder cell proliferation.

RESULTS

In TIL, CD25(+) cells were enriched in the CD3(+)CD4(+) subset (13 +/- 3%) relative to circulating CD3(+)CD4(+) T cells (3 +/- 0.7%) in HNSCC patients (P < or = 0.01) or normal controls (2 +/- 1.5%; P < or = 0.001). Among the CD3(+)CD4(+) subset, CD25(high) Treg represented 3 +/- 0.5% in TIL, 1 +/- 0.3% in PBMC, and 0.4 +/- 0.2% in normal controls. Tregs in TIL were GITR(+), IL-10(+), and TGF-beta1(+), although circulating Treg up-regulated CD62L and CCR7 but not GITR, IL-10, or TGF-beta1. Treg in TIL mediated stronger suppression (P < or = 0.001) than Treg in PBMC of HNSCC patients. The addition of neutralizing IL-10 and TGF-beta antibodies almost completely abrogated suppression (5 +/- 2.51%). Transwell inserts partly prevented suppression (60 +/- 5% versus 95 +/- 5%).

CONCLUSIONS

Suppression in the tumor microenvironment is mediated by a unique subset of Treg, which produce IL-10 and TGF-beta1 and do not require cell-to-cell contact between Treg and responder cells for inhibition.

摘要

目的

免疫抑制，包括由CD4(+)CD25(高)Foxp3(+)调节性T细胞（Treg）介导的免疫抑制，是头颈部鳞状细胞癌（HNSCC）的一个特征。肿瘤浸润淋巴细胞（TIL）中具有独特表型的Treg有助于局部免疫抑制。

实验设计

比较了15例HNSCC患者TIL和/或外周血单个核细胞（PBMC）中Treg的频率和表型以及15例正常对照的PBMC。通过与羧基荧光素二乙酸琥珀酰亚胺酯标记并激活的自体CD4(+)CD25(-)应答T细胞共培养，对单细胞分选的CD4(+)CD25(高)T细胞的调节功能进行检测。使用Transwell小室将Treg与应答细胞分开，并使用中和白细胞介素-10（IL-10）或转化生长因子-β1（TGF-β1）抗体来评估Treg抑制应答细胞增殖所采用的机制。

结果

在TIL中，相对于HNSCC患者循环中的CD3(+)CD4(+)T细胞（3±0.7%）或正常对照（2±1.5%；P≤0.001），CD25(+)细胞在CD3(+)CD4(+)亚群中富集（13±3%）（P≤0.01）。在CD3(+)CD4(+)亚群中，CD25(高)Treg在TIL中占3±0.5%，在PBMC中占1±0.3%，在正常对照中占0.4±0.2%。TIL中的Treg是糖皮质激素诱导的肿瘤坏死因子受体（GITR）(+)、IL-10(+)和TGF-β1(+)，尽管循环中的Treg上调了CD62L和CCR7，但没有上调GITR、IL-10或TGF-β1。TIL中的Treg比HNSCC患者PBMC中的Treg介导更强的抑制作用（P≤0.001）。添加中和IL-10和TGF-β抗体几乎完全消除了抑制作用（5±2.51%）。Transwell小室部分地阻止了抑制作用（60±5%对95±5%）。