title: Tumor-released Galectin-3, a soluble inhibitory ligand of human NKp30, plays an important role in tumor escape from NK cell attack.
abstract: Human Galectin-3 (Gal-3), a β-galactoside-binding protein expressed by tumor cells, has been reported to act as an immune regulator in antitumor T cells. However, its effect on natural killer (NK) cells is elusive. Using a recombinant human NK cell-activating receptor, NKp30 fusion protein (NKp30-Fc), we found that soluble NKp30-Fc could immunoprecipitate Galectin-3. The direct interaction between NKp30 and Galectin-3 was further confirmed using surface plasmon resonance experiments. Because Galectin-3 was mainly released from tumor cells in a soluble form in our study, the binding assay was performed to show that soluble Galectin-3 specifically bound to NK cells and NKp30 on the surface of the NK cells. Functionally, when soluble Galectin-3 was added to the NK-tumor cell coculture system, the NKp30-mediated, but not NKG2D-mediated, cytolysis and CD107a expression in the NK cells were inhibited, and these phenotypes could be restored by preincubation of soluble Galectin-3 with NKp30-Fc fusion protein or the addition of anti-Gal-3 antibody alone. Moreover, genetic down-regulation of Galectin-3 (shGal-3) resulted in tumor cells being more sensitive to NK cell lysis, and, reversely, Galectin-3-overexpressing HeLa cells (exGal-3) became less sensitive to NK cell killing. The results of these in vitro experiments were supported by studies in shGal-3-HeLa or exGal-3-HeLa xenograft non-obese diabetic/severe combined immunodeficiency mice after NK cell adoptive immunotherapy, indicating that Galectin-3 strongly antagonizes human NK cell attack against tumors in vivo. These findings indicate that Galectin-3 may function as an immune regulator to inhibit NK cell function against tumors, therefore providing a new therapeutic target for tumor treatment.
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and.
authors.forename: Huaijian
authors.initials: H
authors.lastname: Guo
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Geng
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and the Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and the Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China sunr@ustc.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: From the Institute of Immunology and Key Laboratory of the China Academy of Sciences (CAS) of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China and the Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D001798:Blood Proteins; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D037502:Galectin 3 / Q000235:genetics / Q000276:immunology*; D037161:Galectins; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D007111:Immunity, Cellular; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C527085:KLRK1 protein, human; C428445:LGALS3 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055628:Natural Cytotoxicity Triggering Receptor 3; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins
keywords: Galectin; Immunosuppression; Natural Killer Cells (NK Cells); Tumor; Tumor Therapy