Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage
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Roberto Arriga1, Sara Caratelli2, Andrea Coppola1, Giulio Cesare Spagnoli3, Adriano Venditti4, Sergio Amadori4, Giulia Lanzilli2, Davide Lauro1, Patrizia Palomba4, Tommaso Sconocchia2, Maria Ilaria Del Principe4, Luca Maurillo4, Francesco Buccisano4, Barbara Capuani1, Soldano Ferrone5, Giuseppe Sconocchia2
1Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
2Laboratory of Tumor Immunology and Immunotherapy, Institute of Translational Pharmacology, Department of Biomedicine, National Research Council (CNR), Rome, Italy
3Institute for Surgical Research and Hospital Management, Department of Biomedicine, University of Basel, Basel, Switzerland
4Hematology, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
5Departments of Surgery and Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Giuseppe Sconocchia, e-mail: firstname.lastname@example.org
Keywords: NK cell, acute myeloid leukemia, CD16, TIMP3, NK cell abnormalities
Received: November 18, 2015 Accepted: November 23, 2015 Published: December 09, 2015
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.
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