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

William H D Hallett1, Erik Ames, Milad Motarjemi

  • 1Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada, Reno, NV 89557, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|December 22, 2007
PubMed

Insights

Bortezomib, a proteasome inhibitor, enhances tumor cell sensitivity to natural killer (NK) cell-mediated killing through TRAIL and FasL pathways. Combining proteasome inhibition with NK cell therapy may improve antitumor efficacy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Bortezomib is a proteasome inhibitor with direct antitumor effects.
  • Bortezomib can sensitize tumor cells to TRAIL-mediated killing.
  • Natural Killer (NK) cells are potent antitumor effector cells.

Purpose of the Study:

  • To investigate if bortezomib sensitizes tumor cells to NK cell-mediated killing.
  • To elucidate the mechanisms underlying bortezomib's effect on NK cell cytotoxicity.
  • To evaluate the therapeutic potential of combining bortezomib with NK cell therapy.

Main Methods:

  • Tumor cells were preincubated with bortezomib.
  • Short-term and 24-hour NK cell killing assays were performed, including with perforin-deficient NK cells.
  • Tumor outgrowth and tumor purging assays in mice were utilized.
  • Expression of Fas and DR5 on tumor cells was analyzed.

Main Results:

  • Bortezomib alone did not affect short-term NK cell killing.
  • Increased tumor cell killing by perforin-deficient NK cells was observed, dependent on TRAIL and FasL.
  • This correlated with increased Fas and DR5 expression on tumor cells.
  • Combination therapy with bortezomib and NK cells led to significant tumor-free survival in mice.

Conclusions:

  • Bortezomib sensitizes tumor cells to NK cell-mediated killing via TRAIL and FasL pathways.
  • The combination of proteasome inhibition with NK cell therapy demonstrates increased antitumor efficacy.
  • This suggests a promising therapeutic strategy for cancer treatment.

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