Bortezomib augments natural killer cell targeting of stem-like tumor cells

Jesus I. Luna, Steven K. Grossenbacher, Ian R. Sturgill, Erik Ames, Sean J. Judge, Lyes A. Bouzid, Morgan Darrow, William J Murphy, Robert J Canter

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.

Original languageEnglish (US)
Article number85
JournalCancers
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2019

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Neoplastic Stem Cells
Natural Killer Cells
Neoplasms
Major Histocompatibility Complex
Aldehyde Dehydrogenase
Proteasome Inhibitors
Adoptive Transfer
Staphylococcal Protein A
Hematologic Neoplasms
Glioblastoma
Bortezomib
Heterografts
Up-Regulation
Radiotherapy
Neoplasm Metastasis
Ligands
Recurrence
Drug Therapy
Growth

Keywords

  • Aldh
  • Bortezomib
  • Brain tumor
  • Cancer stem cell
  • Natural killer cells
  • Pancreatic cancer
  • Sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Luna, J. I., Grossenbacher, S. K., Sturgill, I. R., Ames, E., Judge, S. J., Bouzid, L. A., ... Canter, R. J. (2019). Bortezomib augments natural killer cell targeting of stem-like tumor cells. Cancers, 11(1), [85]. https://doi.org/10.3390/cancers11010085

Bortezomib augments natural killer cell targeting of stem-like tumor cells. / Luna, Jesus I.; Grossenbacher, Steven K.; Sturgill, Ian R.; Ames, Erik; Judge, Sean J.; Bouzid, Lyes A.; Darrow, Morgan; Murphy, William J; Canter, Robert J.

In: Cancers, Vol. 11, No. 1, 85, 01.01.2019.

Research output: Contribution to journalArticle

Luna, JI, Grossenbacher, SK, Sturgill, IR, Ames, E, Judge, SJ, Bouzid, LA, Darrow, M, Murphy, WJ & Canter, RJ 2019, 'Bortezomib augments natural killer cell targeting of stem-like tumor cells', Cancers, vol. 11, no. 1, 85. https://doi.org/10.3390/cancers11010085
Luna JI, Grossenbacher SK, Sturgill IR, Ames E, Judge SJ, Bouzid LA et al. Bortezomib augments natural killer cell targeting of stem-like tumor cells. Cancers. 2019 Jan 1;11(1). 85. https://doi.org/10.3390/cancers11010085
Luna, Jesus I. ; Grossenbacher, Steven K. ; Sturgill, Ian R. ; Ames, Erik ; Judge, Sean J. ; Bouzid, Lyes A. ; Darrow, Morgan ; Murphy, William J ; Canter, Robert J. / Bortezomib augments natural killer cell targeting of stem-like tumor cells. In: Cancers. 2019 ; Vol. 11, No. 1.
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