Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D-NKG2DL dependent manner.
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.
Clinical Research Department, Spanish National Cancer Research Centre CNIO, C/Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
L
L
Fernández
Tumor Immunology Lab, IdiPAZ, Paseo de la Castellana, 261, 28046 Madrid, Spain.
J
J
Valentín
Pediatrics Lab, Universidad de Navarra, C/Irunlarrea s/n, 31008 Pamplona, Spain.
M
M
Zalacain
Bone Marrow and Cell Therapy, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
W
W
Leung
Pediatrics Lab, Universidad de Navarra, C/Irunlarrea s/n, 31008 Pamplona, Spain.
A
A
Patiño-García
Pediatric Hemato-Oncology, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain. Electronic address: aperezmartinez@salud.madrid.org.
A
A
Pérez-Martínez
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D008024:Ligands; D008213:Lymphocyte Activation; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012516:Osteosarcoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D013148:Spironolactone / Q000494:pharmacology; D013997:Time Factors
D000970:Antineoplastic Agents; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D013148:Spironolactone
Immunotherapy; NKG2D–NKG2DL interactions; Natural killer cells; Osteosarcoma tumor initiating cells