A novel concept of adoptive immunotherapy with tumor necrosis factor-related, apoptosis-inducing, ligand-expressing natural killer cells for eliciting an anti-breast-cancer response.

Abstract

e13048 Background: Previous studies have demonstrated that natural killer (NK) cells can destroy breast cancer cells. In the present study, we have reported that liver NK cells exhibit greater cytotoxic activity against tumor cells than do peripheral blood (PB) NK cells in humans. Methods: We investigated the phenotypic and functional properties of NK cells extracted from liver perfusates of living donors in clinical liver transplantation. Next, the susceptibility of various breast cancer cell lines to the activity of the liver and PB NK cells was tested. Results: Stimulation with IL-2 increased the expression of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on both the PB and liver NK cells. Accordingly, both the liver and PB NK cells exhibited strong cytotoxicity against various breast cancer cell lines (MDA-MB231, MDA-MB453, MDA-MB468, and MCF-7) after in vitro stimulation with IL-2. Further treatment with anti-HER2 monoclonal antibodies (mAbs) remarkably promoted the NK cell-mediated cytotoxicity toward the HER2-expressing breast cancer cell line MDA-MB453. All the breast cancer cell lines expressed remarkable levels of a death-inducing TRAIL receptor—death receptor (DR)4 and 5—which contains cytoplasmic death domains and mediates apoptosis, but they did not express the death-inhibitory receptors (DcRs) 1 and 2. Treatment with anti-TRAIL neutralizing mAbs partially reduced the liver and PB NK cell-mediated cytotoxicity toward breast cancer cells (32% ± 9%, 64% ± 15% reduction respectively at E:T = 5:1); this finding indicated the involvement of TRAIL-induced NK cell-mediated cytotoxicity. The expression of CXC chemokine receptor 3 (CXCR3), which binds to chemokines CXCL9, CXCL10, and CXCL11 secreted by breast cancer cells, was upregulated in the IL-stimulated NK cells. Conclusions: TRAIL+ NK cells kill breast cancer cells via death receptor/ligand interactions. This finding provides the basis for a novel concept, i.e., adoptive transfer of IL-2-stimulated NK cells to breast cancer patients for eliciting an anti-breast-cancer response. No significant financial relationships to disclose.