Upregulation of T-cell Immunoglobulin and Mucin-Domain Containing-3 (Tim-3) in Monocytes/Macrophages Associates with Gastric Cancer Progression

ABSTRACT

T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) is an important immune regulatory molecule in cancer immune system. However, expression and function of Tim-3 in monocytes/macrophages in cancer progression mainly remain unclear. In this study, we analyzed Tim-3 levels in peripheral blood mononuclear cells (PBMCs) from 62 gastric cancer patients and 45 healthy controls using flow cytometry and then associated Tim-3 levels with clinical pathological data from patients. We found Tim-3 level was significantly upregulated in monocytes from gastric cancer patients compared with those from healthy controls, and that upregulated Tim-3 levels associated with depth of tumor invasion and tumor lymph node metastasis and advanced clinical stages of gastric cancer patients. Furthermore, tumor-bearing mouse experiments revealed that Tim-3 level on monocytes/macrophages associated with xenograft formation and growth. In addition, culture of monocytes from healthy controls with gastric cancer cell-conditioned medium upregulated Tim-3 expression, but IL-10, TNF-α, IFN-γ, or GM-CSF treatment or T-bet, Eomes, and T-bet/Eomes double gene knockout did not affect Tim-3 levels in blood monocytes/macrophages from human or mouse, respectively. Gal-9/Tim-3 signal was able to significantly stimulate monocyte to secrete IL-6, IL-8, and IL-10, but not IL-1β, IL-12p70, or TNF-α in presence of LPS. In conclusion, our study demonstrated that Tim-3 expressed by monocyte/macrophages might be an important mechanism in gastric cancer progression.

KEYWORDS:

• Gastric cancer
• monocyte/macrophage
• Tim-3
• tumor progression

Acknowledgments

The authors thank Medjaden Bioscience Limited (Hong Kong, China) for providing help to improve the English of this manuscript.

Declaration of interest

The authors declare no conflict of interest in this work.

Funding

This work was partly supported by the National Natural Science Foundation of China (grant number 81272737 to Weichang Chen) and by the Natural Science Foundation of Jiangsu (grant number BK20131158 to Guangbo Zhang).

Additional information

Funding

This work was partly supported by the National Natural Science Foundation of China (grant number 81272737 to Weichang Chen) and by the Natural Science Foundation of Jiangsu (grant number BK20131158 to Guangbo Zhang).