title: Bortezomib enhances antigen-specific cytotoxic T cell responses against immune-resistant cancer cells generated by STAT3-ablated dendritic cells.
abstract: Dendritic cell (DC)-based vaccines have received attention as a new therapeutic modality against cancer. However, increased STAT3 activity in the tumor microenvironment makes DCs tolerogenic and suppresses their antitumor activity. In this study, we explored the effects of a combination treatment consisting of a proteasome inhibitor, bortezomib, and an antigen specific STAT3-ablated (STAT3⁻/⁻) DC-based vaccine on the control of TC-1(P3) tumors, a p53-degraded immune resistant cancer cells. We found that E7-antigen expressing STAT3⁻/⁻ DC (E7-DC-1STAT3⁻/⁻) vaccination enhanced generation of E7-specific CD8⁺ T cells, but was not enough to control TC-1(P3) cancer cells. Therefore, we investigated whether bortezomib could create a synergistic effect with E7-DC-1STAT3⁻/⁻ vaccination. We found that apoptosis via down-regulation of STAT3 and NF-κB and up-regulation of Fas and death receptor 5 (DR5) expression in TC-1(P3) induced by bortezomib was independent of p53 status. We also observed that TC-1(P3) cells pretreated with bortezomib had markedly enhanced anti-tumor effects on E7-specific CD8⁺ T cells through a Fas/DR5-mediated mechanism. In addition, TC-1(P3) tumor-bearing mice treated with bortezomib prior to vaccination with E7-DC-1STAT3⁻/⁻ demonstrated enhanced generation of E7-specific CD8⁺ T cells and prolonged survival compared to those treated with monotherapy. These results suggest that the anti-tumor effects against a p53-degraded immune resistant variant generated by antigen-expressing STAT3-ablated mature DCs may be enhanced by bortezomib via death receptor-mediated apoptosis.
authors: Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
authors: Jee-Eun
authors: JE
authors: Kim
authors: Dong-Hoon
authors: DH
authors: Jin
authors: Wang Jae
authors: WJ
authors: Lee
authors: Daeyoung
authors: D
authors: Hur
authors: T-C
authors: TC
authors: Wu
authors: Daejin
authors: D
authors: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D001897:Boronic Acids; D019496:Cancer Vaccines; D061988:Proteasome Inhibitors; D011719:Pyrazines; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib