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 journalArticle

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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 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
Volume195
Issue number8
DOIs
StatePublished - Oct 15 2015

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Neoplastic Stem Cells
Natural Killer Cells
Phenotype
Neoplasms
Tumor Burden
Pancreatic Neoplasms
Ligands
Cell Line
Death Domain Receptors
Hematopoietic Stem Cells
Coculture Techniques
Heterografts
Aldehydes
Immunotherapy
Cell Survival
Seeds
Up-Regulation
Stem Cells
Neoplasm Metastasis
Transplants

ASJC Scopus subject areas

  • Immunology

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NK cells preferentially target tumor cells with a cancer stem cell phenotype. / Ames, Erik; Canter, Robert J; Grossenbacher, Steven K.; Mac, Stephanie; Chen, Mingyi; Smith, Rachel C.; Hagino, Takeshi; Perez-Cunningham, Jessica; Sckisel, Gail D.; Urayama, Shiro; Monjazeb, Arta M; Fragoso, Ruben C; Sayers, Thomas J.; Murphy, William J.

In: Journal of Immunology, Vol. 195, No. 8, 15.10.2015, p. 4010-4019.

Research output: Contribution to journalArticle

Ames, E, Canter, RJ, Grossenbacher, SK, Mac, S, Chen, M, Smith, RC, Hagino, T, Perez-Cunningham, J, Sckisel, GD, Urayama, S, Monjazeb, AM, Fragoso, RC, Sayers, TJ & Murphy, WJ 2015, 'NK cells preferentially target tumor cells with a cancer stem cell phenotype', Journal of Immunology, vol. 195, no. 8, pp. 4010-4019. https://doi.org/10.4049/jimmunol.1500447
Ames, Erik ; Canter, Robert J ; Grossenbacher, Steven K. ; Mac, Stephanie ; Chen, Mingyi ; Smith, Rachel C. ; Hagino, Takeshi ; Perez-Cunningham, Jessica ; Sckisel, Gail D. ; Urayama, Shiro ; Monjazeb, Arta M ; Fragoso, Ruben C ; Sayers, Thomas J. ; Murphy, William J. / NK cells preferentially target tumor cells with a cancer stem cell phenotype. In: Journal of Immunology. 2015 ; Vol. 195, No. 8. pp. 4010-4019.
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AU - Mac, Stephanie

AU - Chen, Mingyi

AU - Smith, Rachel C.

AU - Hagino, Takeshi

AU - Perez-Cunningham, Jessica

AU - Sckisel, Gail D.

AU - Urayama, Shiro

AU - Monjazeb, Arta M

AU - Fragoso, Ruben C

AU - Sayers, Thomas J.

AU - Murphy, William J

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N2 - 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.

AB - 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.

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