[show abstract][hide abstract] ABSTRACT: 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.
PLoS ONE 01/2012; 7(2):e30676. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous studies have suggested aberrant expression of membrane B7-H3 in tumor cells. This aim of the study was to determine the expression level of soluble B7-H3 (sB7-H3) in circulation and to subsequently evaluate the clinical significance of circulating B7-H3 in patients with non-small cell lung cancer (NSCLC). The level of circulating B7-H3 was determined with ELISA and its correlation with the clinical data was examined. Receiver operating characteristic (ROC) curve analysis was performed to compare the sensitivity and specificity in the diagnosis of NSCLC. Circulating B7-H3 levels in patients with NSCLC were significantly higher than those in patients with other pulmonary diseases (OPD, p<0.001), or those in healthy volunteers (p<0.001). Using a cutoff of 30ng/ml, the sensitivity and specificity of sB7-H3 in differentiating between patients with NSCLC and patients with OPD, and between patients with NSCLC and healthy volunteers was, 48.8 and 98.5%, and 48.0 and 93.7%, respectively. Additionally, higher levels of sB7-H3 were associated with higher tumor stage, tumor size, nodal metastasis, and distant metastasis, but not with sex, age or histological subtype. An area under the curve (AUC) for all stages of NSCLC resulting from sB7-H3 (0.862), which was significantly better than any other tumor markers tested including CA125 (0.621), CA153 (0.571), CA199 (0.459), and CEA (0.638). These results suggest circulating B7-H3 is a valuable biomarker for NSCLC and an elevated level of circulating B7-H3 suggests a poor clinical character for NSCLC.
Lung cancer (Amsterdam, Netherlands) 03/2009; 66(2):245-9. · 3.14 Impact Factor