TIM-3 expression in lymphoma cells predicts chemoresistance in patients with adult T-cell leukemia/lymphoma

Abstract

Abstract. Adult T-cell leukemia/lymphoma (ATLL), an aggressive type of malignant lymphoma, is highly resistant to chemotherapy. However, the detailed mechanisms of the chemoresistance of ATLL have never been elucidated. We previously demonstrated that direct cell-cell interaction between macrophages and lymphoma cells was significantly associated with lymphoma progression in patients with ATLL. The present study aimed to further analyze the effects of cell-cell interaction between macrophages and ATLL cells by means of cell culture studies and immunohistochemical analysis using human ATLL samples. It was found that direct co-culture with macrophages induced chemoresistance in the ATLL ATN-1 cell line, but not in other cell lines, including TL-Mor, ED and ATL-2S. It was also found that expression of the T cell Ig and mucin domain-containing molecule-3 (TIM-3) was induced in ATN-1 cells by their long-term co-culture with macrophages. TIM-3 gene transfection induced chemoresistance in the ATN-1 cells. Immunostaining of ATLL tissues showed TIM-3 expression in 25 out of 58 ATLL cases. Although TIM-3 expression was not associated with overall survival or T classification, it was associated with resistance to chemotherapy. TIM-3 expression is therefore considered to be a marker for predicting the efficacy of chemotherapy, and TIM-3-associated signals may be a therapeutic target for patients with ATLL.

Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression

“…Specifically, Tim-3 is expressed in the Th1 subset, however, it is not expressed on Th2 cells (13,14). The expression of Tim-3 is also present on macrophages, dendritic cells and mast cells (15,16). The mechanisms underlying the immune regulatory reaction of Tim-3 are associated with controlling the functionality of T cell subsets, which occurs by inducing activating or apoptotic signals following interaction with its ligand, galectin-9 (17).…”

Tim-3 promotes cell aggressiveness and paclitaxel resistance through the NF-κB /STAT3 signaling pathway in breast cancer

“…However, there is a high frequency of patients acquiring resistance but the underneath mechanism remains poorly understood. A previous study shows that Tim-3 overexpression induces chemoresistance to adriamycin and carboplatin in lymphoma ATN-1 cells [25]. The Tim-3 expression is increased in patients with head and neck squamous cell carcinoma after combinational chemotherapy (docetaxel, cisplatin and fluorouracil) or pre-radiotherapy [51].…”

“…However, the exact mechanisms of Tim-3 in breast cancer development and progression remain unknown. Additionally, previous studies showed Tim-3 was associated with resistance to anti-angiogenesis drug sunitinib and mTOR inhibitor rapamycin in a renal cell carcinoma cell line [24], and induced chemoresistance to adriamycin and carboplatin in lymphoma ATN-1 cells [25], implying its possible role in tumour angiogenesis and chemoresistance.…”

Cell adhesion molecule-1 (CADM1) expressed on adult T-cell leukemia/lymphoma cells is not involved in the interaction with macrophages.

“…The same set of lymphoma cases of the present study were used in previous studies. 25,26 Immunohistochemistry Briefly, samples were first reacted with anti-CADM1 (x100), anti-CD3 (x1, rabbit monoclonal, Nichirei, Tokyo, Japan), and anti-Iba-1 (also known as allograft inflammatory factor 1; AIF1) (x1000, rabbit polyclonal, WAKO, Tokyo, Japan) antibodies, following which they were incubated with horseradish peroxidase (HRP)-labeled goat anti-rabbit secondary antibodies (Nichirei). Reactions were visualized using the diaminobenzidine substrate system (Nichirei).…”