NK cells preferentially target tumor cells with a cancer stem cell phenotype

Erik Ames, Robert J. Canter, Steven K. Grossenbacher, Stephanie Mac, Mingyi Chen, Rachel C. Smith, Takeshi Hagino, Jessica Perez-Cunningham, Gail D. Sckisel, Shiro Urayama, Arta M. Monjazeb, Ruben C. Fragoso, Thomas J. Sayers, William J. Murphy

Research output: Contribution to journalArticlepeer-review

154 Scopus citations


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 dehydrogenasebright) 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.

Original languageEnglish (US)
Pages (from-to)4010-4019
Number of pages10
JournalJournal of Immunology
Issue number8
StatePublished - Oct 15 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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