title: Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF-βR II and NKG2D.
abstract: The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-β-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon γ (IFN-γ) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-β. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-β. The presence of these modified NK-92 cells significantly inhibited the differentiation of human naïve CD4+T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
authors.forename: Zhongjuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
authors.forename: Linghua
authors.initials: L
authors.lastname: Guo
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Lin
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Institute of Blood and Marrow Transplantation, Department of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.|Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, 28 Medical Dr., Singapore, 117456, Singapore.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, 28 Medical Dr., Singapore, 117456, Singapore.
authors.forename: Dedy
authors.initials: D
authors.lastname: Sandikin
authors.affiliation: Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, 28 Medical Dr., Singapore, 117456, Singapore. micliuh@nus.edu.sg.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000628:therapy*; D002454:Cell Differentiation; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002465:Cell Movement; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D019496:Cancer Vaccines; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Chimeric receptor; Immunotherapy; NK-92 cell; NKG2D; TGF-βR II