Sensitization of Tumor Cells to NK Cell-Mediated Killing by Proteasome Inhibition

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.

Natural killer cell immune escape in acute myeloid leukemia

“…4,84 The proteasome inhibitor bortezomib and the histone deacetylase inhibitor depsipeptide were also shown to improve NK-cellmediated killing of AML cells through the death-receptor pathway TNF-related apoptosis-inducing ligand (TRAIL). 105,106 Improve NK cell crosstalk with other immune cells and promote trafficking Several studies now indicate that a higher IFN-g-producing capacity of NK cells is associated with favorable anti-tumor immunity. 4,9 In general, supporting the NK cell regulatory function was demonstrated to be important for crosstalk with DC and T cells to boost adaptive immunity.…”

Cancer Vaccination at Older Age

“…However, NK cells can also be used to kill tumor cells through other pathways than perforin-mediated tumor cell destruction. For instance, a clinical trial is ongoing with bortezomib which sensitizes tumor cells for TRAIL-and FasL-mediated destruction by NK cells in cancer patients between 20 and 70 years (NCT00720785) [29]. We found NK cell responses (producing IFNγ) in vivo in old mice with metastatic breast cancer after vaccination with pcDNA3.1-Mage-b [3], or with Listeria-Mage-b [unpubl.…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…Of these, some have TRAIL has also been combined with proteasome inhibitors to induce apoptosis (Sprick et al, 2002). It is believed that their combinatorial effect is achieved through TRAIL expression on NK cells, though this does not completely explain the increased sensitivity (Hallett et al, 2008). Combination of TRAIL and a proteasome inhibitor is currently undergoing clinical studies in treatment of advanced multiple myeloma, targeting the myeloma cells.…”