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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.
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Submitted October 25, 2006
Accepted February 7, 2007
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
Radek Spisek, Anna Charalambous, Amitabha Mazumder, David H. Vesole, Sundar Jagannath, and Madhav V Dhodapkar*
Laboratory of Tumor Immunology & Immunotherapy, Rockefeller University, New York, NY
Laboratory of Cellular Physiology & Immunology, Rockefeller University, New York, NY
St. Vincent's Cancer Center, New York, NY
* Corresponding author; email: dhodapm{at}mail.rockefeller.edu.
Most anti-cancer chemotherapies are immunosuppressive and induce non-immunogenic 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  -irradiation or steroids, leads to the induction of anti-tumor 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 anti-tumor immunity.
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