title: Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications.
abstract: Most anticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death. Bortezomib, a specific inhibitor of 26S proteasome, has shown clinical activity in several human tumors, including myeloma. Here we show that the uptake of human myeloma cells by dendritic cells (DCs) after tumor cell death by bortezomib, but not gamma irradiation or steroids, leads to the induction of antitumor immunity, including against primary tumor cells, without the need for any additional adjuvants. The delivery of activating signal from bortezomib-killed tumor cells to DCs depends on cell-cell contact between DCs and dying tumor cells and is mediated by bortezomib-induced exposure of heat shock protein 90 (hsp90) on the surface of dying cells. The combination of bortezomib and geldanamycin (an hsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity. These data identify drug-induced exposure of endogenous heat shock proteins on the surface of dying cells as a mechanism of immunogenic death of human tumors. Specific targeting of bortezomib to tumors may enhance their immunogenicity and the induction of antitumor immunity.
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: Radek
authors.initials: R
authors.lastname: Spisek
authors.forename: Anna
authors.initials: A
authors.lastname: Charalambous
authors.forename: Amitabha
authors.initials: A
authors.lastname: Mazumder
authors.forename: David H
authors.initials: DH
authors.lastname: Vesole
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D016227:Benzoquinones / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects*; D005720:Gamma Rays; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D009101:Multiple Myeloma / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D001897:Boronic Acids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011719:Pyrazines; D000069286:Bortezomib; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C001277:geldanamycin