TIM-3 Is Expressed in Melanoma Cells and Is Upregulated in TGF-Beta Stimulated Mast Cells

Abstract

Many studies detect elevated numbers of mast cells in tumors, but it is still controversial whether they are beneficial or detrimental for tumor cells. Furthermore, many tumors, such as melanomas, produce large quantities of transforming growth factor (TGF)-beta and during tumorigenesis the apoptotic and growth-inhibitory effects of TGF-betas are lost. Based on these data we investigated the gene expression changes in TGF-betaI-treated human mast cells with DNA microarray and detected 45 differentially regulated genes, among them T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). As the major sources of TIM-3 ligand galectin-9 are not tumor cells, but rather mast cells, this raises the possibility of an autocrine mechanism resulting in local immunosuppression through the elevated TIM-3 expression by TGF-betaI. Interestingly, not only melanoma tissue sections contained TIM-3-positive mast cells, but we detected this protein also in melanoma cells. Furthermore, TIM-3 was expressed in both WM35 and HT168-M1 melanoma cell lines at a higher level than in isolated epidermal melanocytes, which can contribute to the lower adhering capacity of tumor cells. In conclusion, the immunoregulatory molecule TIM-3 in TGF-beta-stimulated mast cells and melanoma cells may support the survival of this tumor type.

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

“…[27][28][29] While PD-1 was only expressed on tumor cells in 10% of the unpretreated samples, TIM-3 expression was observed on tumor cells in both unpretreated and pretreated samples. More unpretreated samples had TIM-3 C TILs compare with the pretreated, taken into consideration that our number of pretreated samples is rather low.…”

Activation of mitogen activated protein kinase-Erk kinase (MEK) increases T cell immunoglobulin mucin domain-3 (TIM-3) transcription in human T lymphocytes and a human mast cell line

“…Induction of TIM-3 expression has been reported in T cells stimulated with anti-CD3 antibody together with anti-CD28 antibody, and in human primary mast cells treated with TGF-␤ (Hastings et al, 2009;Wiener et al, 2007). To find regulatory molecules for induction of TIM-3 transcription, we analyzed TIM-3 mRNA levels in Jurkat T cells and HMC-1 human mast cells after stimulation with PMA and TGF-␤.…”

“…Its expression has been revealed in many other immune cells including macrophages, dendritic cells, natural killer (NK) cells and mast cells (Ju et al, 2010;Sabatos et al, 2003;Wiener et al, 2007). TIM-3 plays important roles in immune responses by modulating functions of these cells through interaction with its ligands: galectin-9 and/or phosphatidyl serine (Nakayama et al, 2009;Zhu et al, 2005).…”

“…TIM-3 expression is increased by stimulation of T cell receptor signaling pathway using antibodies against CD3 and CD28, or using chemicals such as phorbol myristic acid (PMA) and ionophores (Hastings et al, 2009). In mast cells, TIM-3 expression is enhanced by treatment of tumor growth factor-␤ (TGF-␤) or by stimulation with antibody against Fc RI (Nakae et al, 2007;Wiener et al, 2007). Recently the involvement of T-box transcription factor T-bet and signal transducer and activator of transcription (STAT)-4 in TIM-3 transcription of murine T cells has been reported (Anderson et al, 2010).…”

Endothelial cell-expressed Tim-3 facilitates metastasis of melanoma cells by activating the NF-κB pathway

“…However, recent studies have demonstrated the expression of Tim-3 in other types of cells (10)(11)(12). Moreover, the up-regulation of Tim-3 has been confirmed in different inflammatory diseases (13)(14)(15).…”