Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer
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Benling Xu1,2,*, Long Yuan3,*, Quanli Gao2, Peng Yuan2, Peng Zhao4, Huijuan Yuan5, Huijie Fan1, Tiepeng Li2, Peng Qin2, Lu Han2, Weijia Fang4 and Zhenhe Suo1,6
1 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China
2 Department of Cancer Biotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China
3 Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China
4 Department of Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
5 Department of Endocrinology, Henan Provincial People’s Hospital, Zhengzhou, Henan, P. R. China
6 Department of Pathology, Oslo University Hospital and Clinical Institute, Faculty of Medicine, University of Oslo, Oslo, Norway
* These authors have contributed equally to the work
Zhenhe Suo, email:
Keywords: colorectal cancer; T cell exhaustion; PD-1; Tim-3
Received: March 12, 2015 Accepted: April 22, 2015 Published: May 12, 2015
T-cell exhaustion represents a progressive loss of T-cell function. The inhibitory receptor PD-1 is known to negatively regulate CD8+ T cell responses directed against tumor antigen, but the blockades of PD-1 pathway didn’t show the objective responses in patients with colorectal cancer (CRC). Thus, further exploring the molecular mechanism responsible for inducing T-cell dysfunction in CRC patients may reveal effective strategies for immune therapy. This study aims to characterize co-inhibitory receptors on T cells in CRC patients to identify novel targets for immunotherapy. In this study, peripheral blood samples from 20 healthy controls and 54 consented CRC patients, and tumor and matched paraneoplastic tissues from 7 patients with advanced CRC, subjected to multicolor flow cytometric analysis of the expression of PD-1 and Tim-3 receptors on CD8+ T cells. It was found that CRC patients presented with significantly higher levels of circulating Tim-3+PD-1+CD8+ T cells compared to the healthy controls (medians of 3.12% and 1.99%, respectively, p = 0.0403). A similar increase of Tim-3+PD-1+CD8+ T cells was also observed in the tumor tissues compared to paraneoplastic tussues. Tim-3+PD-1+CD8+ T cells in tumor tissues produced even less cytokine than that in paraneoplastic tissues. Functional ex vivo experiments showed that Tim-3+PD-1+CD8+ T cells produced significantly less IFN-γ than Tim-3-PD-1-CD8+ T cells, followed by Tim-3+PD-1-CD8+ T cells, and Tim-3-PD-1+CD8+ T cells, indicating a stronger inhibition of IFN-γ production of Tim-3+CD8+ T cells . It is also found in this study that Tim-3+PD-1+CD8+ T cell increase in circulation was correlated with clinical cancer stage but not histologic grade and serum concentrations of cancer biomarker CEA. Our results indicate that upregulation of the inhibitory receptor Tim-3 may restrict T cell responses in CRC patients, and therefore blockage of Tim-3 and thus restoring T cell responses may be a potential therapeutic approach for CRC patients.
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