Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D–NKG2DL dependent manner. Issue 1 (1st November 2015)

• Record Type: Journal Article
• Authors: Fernández, L.; Valentín, J.; Zalacain, M.; Leung, W.; Patiño-García, A.; Pérez-Martínez, A.
• Is Part Of: Cancer letters. Volume 368:Issue 1(2016)
• Page Start: 54
• Page End: 63
• Publication Date: 2015-11-01
• Subjects: Natural killer cells -- Osteosarcoma tumor initiating cells -- NKG2D–NKG2DL interactions -- Immunotherapy; DNAM-1 DNA accessory molecule 1 -- EMEM Eagle's minimum essential medium -- Gem gemcitabine -- GFP green-fluorescent protein -- MEM minimum essential medium -- MFI mean fluorescence intensity -- MICA/MICB major histocompatibility complex class I related chains A and B -- MTT metastatic tumors -- NCRs natural cytotoxicity receptors -- NK natural killer cells -- NKAEs activated and expanded natural killer cells -- NKG2D (natural-killer group-2 member D) receptor -- NKG2DL NKG2D ligands -- OS osteosarcoma -- PBMC peripheral blood mononuclear cells -- SCGM stem cell growth medium -- SDF-1 stromal cell-derived factor -- SPIR spironolactone -- TICs tumor initiating cells -- ULBP UL 16 binding protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.07.042
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: NK cells ability to target osteosarcoma cells and the pathways involved were studied. We explored NK cell elimination of osteosarcoma (OS) Tumor Initiating Cells (TICs). NKG2D–NKG2DL pathway is involved in NK cell elimination of OS cells, including TICs. NK cells reduce tumor volume, metastasis and improve survival in an OS animal model. Abstract: Current therapies fail to cure most metastatic or recurrent bone cancer. We explored the efficacy and the pathways involved in natural killer (NK) cells' elimination of osteosarcoma (OS) cells, including tumor initiating cells (TICs), which are responsible for chemotherapy resistance, recurrence, and metastasis. The expression of ligands for NK cell receptors was studied in primary OS cell lines by flow cytometry. In vitro cytotoxicity of activated and expanded NK (NKAE) cells against OS was tested, and the pathways involved explored by using specific antibody blockade. NKAE cells' ability to target OS TICs was analyzed by flow cytometry and sphere formation assays. Spironolactone (SPIR) was tested for its ability to increase OS cells' susceptibility to NK cell lysis in vitro and in vivo . We found OS cells were susceptible to NKAE cells' lysis both in vivo and in vitro, and this cytolytic activity relied on interaction between NKG2D receptor and NKG2D ligands (NKG2DL). SPIR increased OS cells' susceptibility to lysis by NKAE cells, and could shrink the OS TICs. Our results show NKAE cells target OS cells including the TICs compartment, supporting the use of NK-cell based immunotherapies for OS.