title: NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype.
abstract: Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24(+)/CD44(+), CD133(+), and aldehyde dehydrogenase(bright)) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Erik
authors.initials: E
authors.lastname: Ames
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Robert J
authors.identifier: http://orcid.org/0000-0002-3331-5418
authors.initials: RJ
authors.lastname: Canter
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grossenbacher
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mac
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Smith
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hagino
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Jessica
authors.initials: J
authors.lastname: Perez-Cunningham
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA 95817;
authors.forename: Shiro
authors.initials: S
authors.lastname: Urayama
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA 95817;
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Fragoso
authors.affiliation: Basic Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702; and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817; Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA 95817 wmjmurphy@ucdavis.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD