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
Open accessAbstract
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 γ 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.
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Anthracyclins, but not mitomycin C or etoposide, cause tumor cells to expose a CRT-ERp57 complex at a pre-apoptotic stage, facilitating DC uptake.
“Similarly, in response to some chemotherapeutic agents, such as anthracyclins, but not others, such as mitomycin C or etoposide, tumor cells expose complexes that are formed by the chaperone calreticulin (CRT) and the disulfide isomerase ERp57 on their cell surface. The exposure of this complex occurs at a pre-apoptotic stage and facilitates the uptake of dying cells by DC 7,39.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [39]
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References 32 · Cited by 388
Research works printed but not linked: 2
- Kukreja A, Hutchinson A, Mazumder A, et al. Bort- ezomib disrupts tumor-dendritic cell interactions in myeloma and lymphoma: therapeutic implica- tions. Br J Haematology. 2006;136:106-110.
- Dhodapkar K, Krasovsky J, Williamson B, Dhodapkar M. Anti-tumor monoclonal antibodies enhance cross presentation of cellular antigens and the generation of tumor specific killer T cells by dendritic cells. J Exp Med. 2002;195:125-133.
- Authors
- Spisek, R., Charalambous, A., Mazumder, A., Vesole, D. H., Jagannath, S., & Dhodapkar, M. V.
- Affiliations
- Laboratory of Tumor Immunology and Immunotherapy and
- Rockefeller University (US)
- Saint Vincent's Catholic Medical Center (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-06-01
- Volume
- 109
- Issue
- 11
- Pages
- 4839-4845
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1885516
- OpenAlex
- W1987331911
- Cited by
- 388
- References
- 32
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 12 · 2023: 24 · 2022: 24 · 2021: 22 · 2020: 27 · 2019: 16 · 2018: 20 · 2017: 19 · 2016: 20 · 2015: 33 · 2014: 21 · 2013: 21 · 2012: 26
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- National Cancer Institute (CA 106802, CA109465, R01CA109465, R01CA106802)
- National Center for Complementary and Integrative Health (P50AT002779, P50 AT 02779)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- bortezomib, dendritic cells, multiple myeloma, HSP90, immunogenic cell death, tumor immunogenicity, proteasome inhibitors, geldanamycin, antitumor immunity, cancer cell death
- MeSH terms
- Bortezomib, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Dendritic Cells, Gamma Rays, Humans, Interferon-gamma, Leukocytes, Mononuclear, Multiple Myeloma, Neoplasms, Pyrazines, Benzoquinones, Apoptosis, HSP90 Heat-Shock Proteins, Cell Line, Tumor, Proteasome Endopeptidase Complex, Lactams, Macrocyclic
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