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

被引:177
作者
Ames, Erik [1 ]
Canter, Robert J. [2 ]
Grossenbacher, Steven K. [1 ]
Mac, Stephanie [1 ]
Chen, Mingyi [3 ]
Smith, Rachel C. [1 ]
Hagino, Takeshi [1 ]
Perez-Cunningham, Jessica [1 ]
Sckisel, Gail D. [1 ]
Urayama, Shiro [4 ]
Monjazeb, Arta M. [5 ]
Fragoso, Ruben C. [5 ]
Sayers, Thomas J. [6 ]
Murphy, William J. [1 ,7 ]
机构
[1] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA
[2] Univ Calif Davis, Sch Med, Dept Surg, Div Surg Oncol, Sacramento, CA 95817 USA
[3] Univ Calif Davis, Sch Med, Dept Pathol & Lab Med, Sacramento, CA 95817 USA
[4] Univ Calif Davis, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Sacramento, CA 95817 USA
[5] Univ Calif Davis, Sch Med, Dept Radiat Oncol, Sacramento, CA 95817 USA
[6] Leidos Biomedical Res Inc, Frederick Natl Lab, Basic Sci Program, Frederick, MD 21702 USA
[7] Univ Calif Davis, Med Ctr, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA
基金
美国国家卫生研究院;
关键词
NATURAL-KILLER-CELLS; GROWTH; CYTOTOXICITY; RECEPTORS; LIGANDS;
D O I
10.4049/jimmunol.1500447
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:4010 / 4019
页数:10
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