Yonago Acta medica 2012;55:1–9
Upregulation of TIM-3 and PD-1 on CD4+ and CD8+ T Cells Associated with Dysfunction of Cell-Mediated Immunity after Colorectal Cancer Operation
Yosuke Arai, Hiroaki Saito and Masahide Ikeguchi
Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
Surgery has been reported to suppress cell-mediated immunity; however, the detailed mechanisms responsible for this remain unclear. We obtained information on expressions of T-cell immunoglobulin domain and mucin domain 3 (TIM-3) and programmed cell death 1 (PD-1) on both CD4+ and CD8+ T cells postoperatively from colorectal cancer patients and evaluated by multicolor flow cytometry. The functions of CD4+ and CD8+ T cells based on TIM-3 and PD-1 expressions were determined by quantitating the concentration of interferon-γ (IFN-γ) by enzyme-linked immunosorbent assay. The study demonstrated a rapid and significant decrease in number of total lymphocytes, CD4+ T cells and CD8+ T cells. These immune cells reached the minimum on day 1 and then increased, but still significantly decreased on days 3 and 7. The frequency of PD-1+CD4+ T cells and TIM-3+CD4+ T cells significantly increased after colorectal surgery. IFN-γ secretion by PD-1+TIM-3+CD4+ T cells was significantly decreased compared to secretion by either PD-1+TIM3-CD4+ T cells or PD-1−TIM-3−CD4+ T cells. Furthermore, IFN-γ secretion by PD-1+TIM-3+CD8+ T cells was significantly decreased compared to secretion by either PD-1−TIM-3+CD8+ T cells or PD-1−TIM-3−CD8+ T cells. The expression of PD-1 and TIM-3 was closely related to impaired cell-mediated immunity that was observed after surgery for colorectal cancer. New treatment targeting TIM-3 and PD-1 on CD4+ and CD8+ T cells during the perioperative period may provide a breakthrough in the treatment of colorectal cancer patients.
Key words: colorectal cancer; programmed cell death 1; surgical trauma; T-cell immunoglobulin domain and mucin domain 3
