Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer.

Benling Xu,Lu Han,Zhenhe Suo,Weijia Fang,Tiepeng Li,Huijuan Yuan,Huijie Fan,Long Yuan,Peng Qin,Quanli Gao,Peng Zhao,Peng Yuan

doi:10.18632/oncotarget.4112

Abstract

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.

Highlights

RESULTScolorectal cancer (CRC) is the third most common cancer in women and the fourth most common in men worldwide [1]
To further determine whether other molecular pathways are involved in T cell dysfunction in CRC patients, we studied Tim-3 and PD-1 expression on CD8+ T cells of circulating, tumor-infiltrating lymphocytes (TILs) and paraneoplastic tissues from patients with CRC and investigated clinical relevance of co-inhibitory molecules in circulating and TILs in CRC
Infiltrating CD4+ Th1 cells and CD8+ cytotoxic T cells sign a positive prognosis in CRC [20, 21], these lymphocytes often can’t kill tumor cells

Summary

Introduction

CRC is the third most common cancer in women and the fourth most common in men worldwide [1]. Incidence of and mortality from CRC are increasing in China in recent years. It is very important to look for a new method to improve the effect of the treatment of CRC. Especially T lymphocytes, plays an important role in eliminating or controlling cancer [3], while the tumor microenvironment can be immunosuppressive. Several lines of evidence support the finding that T cell antitumor function is impaired in CRC patients [4, 5]. Characterisation of the mechanism and molecules involved in the regulation of T cell responses will be valuable in the diagnosis and therapeutics of cancer

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