Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage

Arriga, RobertoCaratelli, SaraCoppola, AndreaSpagnoli, Giulio CesareVenditti, AdrianoAmadori, SergioLanzilli, GiuliaLauro, DavidePalomba, PatriziaSconocchia, TommasoDel Principe, Maria IlariaMaurillo, LucaBuccisano, FrancescoCapuani, BarbaraFerrone, SoldanoSconocchia, Giuseppe2016-05-022016Arriga, R., S. Caratelli, A. Coppola, G. C. Spagnoli, A. Venditti, S. Amadori, G. Lanzilli, et al. 2016. “Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage.” Oncotarget 7 (2): 2070-2079.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:26860115Acute 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.en-USNK cellacute myeloid leukemiaCD16TIMP3NK cell abnormalitiesEnhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damageJournal Article2016-05-02