Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou, People's Republic of China.
PLoS One. 2012;7(2):e30676. doi: 10.1371/journal.pone.0030676. Epub 2012 Feb 17.
T cell immunoglobulin-3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. TIM-3 is upregulated in exhausted CD8(+) T cells in both chronic infection and tumor. However, the nature of TIM-3(+)CD4(+) T cells in the tumor microenvironment is unclear. This study is to characterize TIM-3 expressing lymphocytes within human lung cancer tissues and establish clinical significance of TIM-3 expression in lung cancer progression.
A total of 51 human lung cancer tissue specimens were obtained from pathologically confirmed and newly diagnosed non-small cell lung cancer (NSCLC) patients. Leukocytes from tumor tissues, distal normal lung tissues, and peripheral blood mononuclear cells (PBMC) were analyzed for TIM-3 surface expression by flow cytometry. TIM-3 expression on tumor-infiltrating lymphocytes (TILs) was correlated with clinicopathological parameters.
TIM-3 is highly upregulated on both CD4(+) and CD8(+) TILs from human lung cancer tissues but negligibly expressed on T cells from patients' peripheral blood. Frequencies of IFN-γ(+) cells were reduced in TIM-3(+)CD8(+) TILs compared to TIM-3(-)CD8(+) TILs. However, the level of TIM-3 expression on CD8(+) TILs failed to associate with any clinical pathological parameter. Interestingly, we found that approximately 70% of TIM-3(+)CD4(+) TILs expressed FOXP3 and about 60% of FOXP3(+) TILs were TIM-3(+). Importantly, TIM-3 expression on CD4(+) T cells correlated with poor clinicopathological parameters of NSCLC such as nodal metastasis and advanced cancer stages. Our study reveals a new role of TIM-3 as an important immune regulator in the tumor microenvironment via its predominant expression in regulatory T cells.
T 细胞免疫球蛋白 3（TIM-3）已被确立为负调控分子，在免疫耐受中发挥关键作用。在慢性感染和肿瘤中，耗尽的 CD8（+）T 细胞中 TIM-3 上调。然而，肿瘤微环境中 TIM-3（+）CD4（+）T 细胞的性质尚不清楚。本研究旨在描述人类肺癌组织中表达 TIM-3 的淋巴细胞，并确定 TIM-3 表达在肺癌进展中的临床意义。
从病理证实的新诊断的非小细胞肺癌（NSCLC）患者中获得总共 51 例人肺癌组织标本。通过流式细胞术分析肿瘤组织、远端正常肺组织和外周血单个核细胞（PBMC）中的白细胞上的 TIM-3 表面表达。分析肿瘤浸润淋巴细胞（TIL）上的 TIM-3 表达与临床病理参数的相关性。
TIM-3 在人类肺癌组织中的 CD4（+）和 CD8（+）TIL 上高度上调，但在患者外周血中的 T 细胞上表达可忽略不计。与 TIM-3（-）CD8（+）TIL 相比，TIM-3（+）CD8（+）TIL 中的 IFN-γ（+）细胞频率降低。然而，CD8（+）TIL 上 TIM-3 表达水平与任何临床病理参数均无关。有趣的是，我们发现大约 70%的 TIM-3（+）CD4（+）TIL 表达 FOXP3，约 60%的 FOXP3（+）TIL 是 TIM-3（+）。重要的是，CD4（+）T 细胞上 TIM-3 的表达与 NSCLC 的不良临床病理参数相关，如淋巴结转移和晚期癌症分期。我们的研究揭示了 TIM-3 通过在调节性 T 细胞中主要表达作为肿瘤微环境中重要免疫调节剂的新作用。
