title: Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage.
abstract: Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell-based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37°C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy of AML with haploidentical NK cells.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Arriga
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Institute of Translational Pharmacology, Department of Biomedicine, National Research Council (CNR), Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caratelli
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Coppola
authors.affiliation: Institute for Surgical Research and Hospital Management, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Giulio Cesare
authors.initials: GC
authors.lastname: Spagnoli
authors.affiliation: Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.affiliation: Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Institute of Translational Pharmacology, Department of Biomedicine, National Research Council (CNR), Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Lanzilli
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.affiliation: Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Palomba
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Institute of Translational Pharmacology, Department of Biomedicine, National Research Council (CNR), Rome, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Sconocchia
authors.affiliation: Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Maria Ilaria
authors.initials: MI
authors.lastname: Del Principe
authors.affiliation: Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Maurillo
authors.affiliation: Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Buccisano
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Capuani
authors.affiliation: Departments of Surgery and Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Institute of Translational Pharmacology, Department of Biomedicine, National Research Council (CNR), Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: CD16; NK cell; NK cell abnormalities; TIMP3; acute myeloid leukemia