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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4839-4845. Prepublished online as a Blood First Edition Paper on February 13, 2007; DOI 10.1182/blood-2006-10-054221.
IMMUNOBIOLOGY 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 implications1 Laboratory of Tumor Immunology and Immunotherapy and 2 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY; 3 St Vincent's Cancer Center, New York, NY
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
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
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. 
