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- Title
A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells.
- Authors
Sarhan, Dhifaf; Wennerberg, Erik; D'Arcy, Padraig; Gurajada, Deepthy; Linder, Stig; Lundqvist, Andreas
- Abstract
The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK ( p < 0.0002) and T cell ( p = 0.02)-mediated cytotoxicity. Treatment with b-AP15 resulted in increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 expression ( p = 0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells ( p = 0.006), T cells ( p < 0.0001) or b-AP15 alone ( p = 0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells ( p ≤ 0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer.
- Subjects
CANCER cells; APOPTOSIS; PROTEASOMES; KILLER cells; T cells; CELL-mediated cytotoxicity; TUMOR necrosis factors; ANTINEOPLASTIC agents
- Publication
Cancer Immunology, Immunotherapy, 2013, Vol 62, Issue 8, p1359
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-013-1439-1