Immune mechanism of the antitumor effects generated by bortezomib.
Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation. Taken together, our data indicate that bortezomib can render tumor cells immunogenic by upregulating the cell surface expression of heat shock protein 60 and heat shock protein 90, as well as improve DC function, which results in potent immune-mediated antitumor effects.
Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City, Taiwan. clchang@mmc.edu.tw
Chih-Long
CL
Chang
Yun-Ting
YT
Hsu
Chao-Chih
CC
Wu
Yuh-Cheng
YC
Yang
Connie
C
Wang
T-C
TC
Wu
Chien-Fu
CF
Hung
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018834:Chaperonin 60 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use*; D015854:Up-Regulation / Q000276:immunology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D019496:Cancer Vaccines; D018834:Chaperonin 60; D018841:HSP90 Heat-Shock Proteins; C107835:Hspca protein, mouse; C557066:Hspd1 protein, mouse; D024101:Mitochondrial Proteins; D011719:Pyrazines; D000069286:Bortezomib