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J Immunol. 2015 Oct 15;195(8):4010-9. doi: 10.4049/jimmunol.1500447. Epub 2015 Sep 11.

NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype.

Author information

1
Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817;
2
Division of Surgical Oncology, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA 95817;
3
Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA 95817;
4
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA 95817;
5
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA 95817;
6
Basic Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702; and.
7
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.

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.

PMID:
26363055
PMCID:
PMC4781667
DOI:
10.4049/jimmunol.1500447
[Indexed for MEDLINE]
Free PMC Article

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