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.
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Acknowledgments We thank Dr. Rolf Kiessling and Helena Tuf-vesson Stiller, for intellectual support, and Juan Castro for assistance with flow cytometry and STR analysis, at the Department of Oncology-Pathology, Stockholm, Sweden. We also thank Dr. Nick Tobin for revising the manuscript. We would also like to thank staff at the animal facility at the Department of Microbiology, Tumor and Cell Biology and The Swedish Institute for Communicable Disease Control, Karolinska Institutet. This work was supported by funding from The Swedish Research Council, The Swedish Cancer Society, The European Research Council, Karolinska Institutet, Jeanssons Stiftel-ser, Åke Wibergs Stiftelse, Magnus Bergvalls Stiftelse, Fredrik och Ingrid Thurings Stiftelse, Stiftelsen Clas Groschinskys Minnesfond and The Swedish Society of Medicine.
- Natural killer cells
- Proteasome inhibitor
- T cells