title: Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma.
abstract: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to play an important role in mediating NK-cell function in human diseases. However, the relationship between Tim-3 expression in natural killer (NK) cells and human lung adenocarcinoma remains unclear. We therefore investigated the expression of Tim-3 in NK cells and explored the effect of Tim-3 blockade on NK cell-mediated activity in human lung adenocarcinoma. Upregulated expression of Tim-3 on CD3-CD56+ cells (P<0.05) and CD3-CD56(dim) cells (P<0.05) of patients with lung adenocarcinoma was detected by flow cytometry. Moreover, Tim-3 expression in CD3-CD56+ NK cells was higher in patients with lung adenocarcinoma with lymph node metastasis (LNM) (P<0.05) or with tumor stage T3-T4 (P<0.05). Tim-3 expression in CD56(dim) NK-cell subset was higher in patients with tumor size ≥3cm (P<0.05), or LNM (P<0.05) or with tumor stage T3-T4 (P<0.05). Further analysis showed that higher expressions of Tim-3 on both CD3-CD56+ NK cells and CD56(dim) NK-cell subset were independently correlated with shorter overall survival of patients with lung adenocarcinoma (log-rank test, P=0.0418, 0.0406, respectively). Importantly, blockade of Tim-3 signaling with anti-Tim-3 antibodies resulted in the increased cytotoxicity and IFN-γ production of peripheral NK cells from patients with lung adenocarcinoma. Our data indicate that Tim-3 expression in NK cells can function as a prognostic biomarker in human lung adenocarcinoma and support that Tim-3 could be a new target for an immunotherapeutic strategy.
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Tan
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: ChangChang
authors.initials: C
authors.lastname: Lu
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Oncology, Cancer Biotherapy Center, Zhejiang Province People's Hospital, Hangzhou, Zhejiang, 310014, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Wu
authors.affiliation: Cell and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China. Electronic address: hospital1234@126.com.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardio-Thoracic Surgery, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhejiang 316000, China. Electronic address: zhoushanzhang1@126.com.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D019002:CD56 Antigen / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D019002:CD56 Antigen; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C522918:NCAM1 protein, human
keywords: Cytotoxicity; Human lung adenocarcinoma; Natural killer cells; T cell immunoglobulin- and mucin-domain-containing molecule-3