Preoperative Tim-3 expression on peripheral NK cells is correlated with pathologic TNM staging in colorectal cancer

Abstract

Previous research has indicated that T cell immunoglobulin and mucin domain 3 (Tim-3) serves an important regulatory role in lymphocytes and in several cancers. However, the association between Tim‑3 expression on various lymphocyte subsets and human colorectal cancer (CRC) has not been elucidated. The present study aimed to characterize Tim‑3 expression on peripheral lymphocytes, including cluster of differentiation CD3+CD56‑ T cells, CD3‑CD56+ natural killer (NK) cells and CD3+CD56+ natural killer T (NKT) cells, in patients with CRC. The frequency of T cells, NK cells and NKT cells expressing Tim‑3 was assessed by multicolor flow cytometry of peripheral blood collected from 36 preoperative CRC patients and 38 healthy donors. The expression of Tim‑3 on lymphocyte subsets from 53 postoperative blood samples of CRC patients was also analyzed. There were fewer circulating NK cells in patients with CRC compared with healthy controls (P=0.0027); NK cell expression of Tim‑3 was also significantly decreased (P=0.0239). The frequency of circulating NK cells and Tim‑3+ NK cells was negatively correlated with clinical cancer stage, compared with healthy controls, but not with other clinicopathological parameters or serum concentrations of CRC biomarkers. Furthermore, the expression of Tim‑3 in NK cells was higher in CRC patients without metastasis. Notably, NK cell Tim‑3 expression in CRC patients was significantly restored following surgical resection of the primary tumor. In conclusion, the present study indicates the presence of an altered frequency and expression of Tim‑3 in peripheral NK cells in CRC patients. Preoperative Tim‑3 expression on peripheral NK cells is correlated with differential staging in colorectal cancer, and may be useful as a serum biomarker.

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“…Here, as well, blocking TIM-3 with antibodies increased NK cell cytotoxicity and cytokine secretion. Additional recent studies identified TIM-3 expression as a marker of NK cell dysfunction and disease severity in colorectal cancer, esophageal cancer, endometrial cancer, and bladder cancer (96,(98)(99)(100)(101). Interestingly, TIM-3 engagement was initially shown to increase the expression of IFN-γ by NK cells in response to galectin-9, the β-galactoside binding lectin (123).…”

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“…Notably, alterations in circulating NK cells frequency, phenotype and function have also been found in tumour patients and have been associated with the clinical outcome . So far, the analysis of peripheral blood NK cells in solid tumours patients showed an association between a suppressed functionally impaired NK cells phenotype and poor prognosis.…”

“…Since Tim‐3 expression is induced by activating cytokines and marks the most cytotoxic NK cell subset with the highest IFN‐γ production, it could act by limiting the duration and magnitude of NK cell responses, thus preventing chronic activation . However, even if Tim‐3 expression on NK cells is usually linked to exhaustion and impaired function, such association may be tumour‐dependent, since colorectal cancer patients show reduced frequencies of Tim‐3 + NK cells negatively correlating with disease stage and increasing after tumour resection …”

“…80 Notably, alterations in circulating NK cells frequency, phenotype and function have also been found in tumour patients and have been associated with the clinical outcome. [81][82][83][84][85][86][87][88][89][90] So far, the analysis of peripheral blood NK cells in solid tumours patients showed an association between a suppressed functionally impaired NK cells phenotype and poor prognosis. Peripheral NK cells from metastatic melanoma patients show an exhausted phenotype, with a high expression of KIRs, low levels of NCRs and downregulation of stimulating cytokines receptors, that result in functional defects in their ability to proliferate, secrete cytokines and kill target cells.…”

“…82 However, even if Tim-3 expression on NK cells is usually linked to exhaustion and impaired function, such association may be tumour-dependent, since colorectal cancer patients show reduced frequencies of Tim-3 + NK cells negatively correlating with disease stage and increasing after tumour resection. 83 In patients affected by digestive cancers and lung adenocarcinoma, tumour progression and survival have been negatively associated with a high expression of inhibitory receptors on NK cells, particularly PD-1 and Tim-3, and with the downregulation of several activating receptors, the latter phenomenon correlating also with TGF-β serum levels and tumour differentiation grade. [84][85][86][87] Conversely, in these patients, survival was positively associated with NKp46 expression.…”