Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition

William H D Hallett, Erik Ames, Milad Motarjemi, Isabel Barao, Anil Shanker, David L. Tamang, Thomas J. Sayers, Dorothy Hudig, William J Murphy

Research output: Contribution to journalArticle

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Abstract

Bortezomib is a proteasome inhibitor that has direct antitumor effects. We and others have previously demonstrated that bortezomib could also sensitize tumor cells to killing via the death ligand, TRAIL. NK cells represent a potent antitumor effector cell. Therefore, we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing. Preincubation of tumor cells with bortezomib had no effect on short-term NK cell killing or purified granule killing assays. Using a 24-h lysis assay, increases in tumor killing was only observed using perforin-deficient NK cells, and this increased killing was found to be dependent on both TRAIL and FasL, correlating with an increase in tumor Fas and DR5 expression. Long-term tumor outgrowth assays allowed for the detection of this increased tumor killing by activated NK cells following bortezomib treatment of the tumor. In a tumor purging assay, in which tumor:bone marrow cell mixtures were placed into lethally irradiated mice, only treatment of these mixtures with a combination of NK cells with bortezomib resulted in significant tumor-free survival of the recipients. These results demonstrate that bortezomib treatment can sensitize tumor cells to cellular effector pathways. These results suggest that the combination of proteasome inhibition with immune therapy may result in increased antitumor efficacy.

Original languageEnglish (US)
Pages (from-to)163-170
Number of pages8
JournalJournal of Immunology
Volume180
Issue number1
StatePublished - Jan 1 2008
Externally publishedYes

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Proteasome Endopeptidase Complex
Natural Killer Cells
Neoplasms
Perforin
Proteasome Inhibitors
Bortezomib
Bone Marrow Cells
Ligands

ASJC Scopus subject areas

  • Immunology

Cite this

Hallett, W. H. D., Ames, E., Motarjemi, M., Barao, I., Shanker, A., Tamang, D. L., ... Murphy, W. J. (2008). Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. Journal of Immunology, 180(1), 163-170.

Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. / Hallett, William H D; Ames, Erik; Motarjemi, Milad; Barao, Isabel; Shanker, Anil; Tamang, David L.; Sayers, Thomas J.; Hudig, Dorothy; Murphy, William J.

In: Journal of Immunology, Vol. 180, No. 1, 01.01.2008, p. 163-170.

Research output: Contribution to journalArticle

Hallett, WHD, Ames, E, Motarjemi, M, Barao, I, Shanker, A, Tamang, DL, Sayers, TJ, Hudig, D & Murphy, WJ 2008, 'Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition', Journal of Immunology, vol. 180, no. 1, pp. 163-170.
Hallett WHD, Ames E, Motarjemi M, Barao I, Shanker A, Tamang DL et al. Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. Journal of Immunology. 2008 Jan 1;180(1):163-170.
Hallett, William H D ; Ames, Erik ; Motarjemi, Milad ; Barao, Isabel ; Shanker, Anil ; Tamang, David L. ; Sayers, Thomas J. ; Hudig, Dorothy ; Murphy, William J. / Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. In: Journal of Immunology. 2008 ; Vol. 180, No. 1. pp. 163-170.
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