Targeting Heat Shock Proteins for Immunotherapy in Multiple Myeloma: Generation of Myeloma-Specific CTLs Using Dendritic Cells Pulsed with Tumor-Derived gp96
Open Access
- 15 December 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 11 (24), 8808-8815
- https://doi.org/10.1158/1078-0432.ccr-05-1553
Abstract
Purpose: To develop effective immunotherapies for patients with multiple myeloma, it is important to use novel tumor antigens. Recent studies in solid tumors show that tumor-derived heat shock proteins (Hsp) can be used as immunogen; however, no such study has yet been reported in multiple myeloma. Experimental Design: We examined whether myeloma-derived Hsp gp96 can be used as a myeloma antigen. Specific CTL lines were obtained after repeatedly stimulating T cells with autologous, HLA-A*0201+ dendritic cells pulsed with gp96 derived from HLA-A*0201+ human myeloma cell line (HMCL) U266 or primary myeloma cells. Results: These T cells lysed not only gp96-pulsed dendritic cells, U266, and other HLA-A*0201+ HMCLs IM-9 and XG1 but also effectively killed HLA-A*0201+ primary myeloma cells from patients. No killing was observed against unpulsed dendritic cells, dendritic cells pulsed with control gp96, HLA-A*0201− HMCLs, and primary myeloma cells, or HLA-A*0201+ nonmyeloma cells. Cytotoxicity was mainly MHC class I/HLA-A*0201 restricted, suggesting that the CTLs recognized gp96-chaperoned peptides on HLA-A*0201 that were derived from shared myeloma antigens and that myeloma cells naturally present these peptides in the context of their surface MHC molecules. Upon antigen stimulation, these T cells secreted IFN-γ and tumor necrosis factor-α, indicating that they belong to type 1 T-cell subsets. Conclusion: These results show that these T cells are potent CTLs that are able to effectively lyse myeloma cells but not normal blood cells and also suggest that Hsps from allogeneic tumor cells may be used as vaccines to immunize patients.Keywords
This publication has 37 references indexed in Scilit:
- Cellular mechanisms governing cross-presentation of exogenous antigensNature Immunology, 2004
- Interaction of Heat Shock Proteins with Peptides and Antigen Presenting Cells: Chaperoning of the Innate and Adaptive Immune ResponsesAnnual Review of Immunology, 2002
- Deletion of Idiotype (Id)-Specific T Cells in Multiple MyelomaActa Oncologica, 2000
- Carboxyfluorescein succinimidyl ester‐based proliferative assays for assessment of T cell function in the diagnostic laboratoryImmunology & Cell Biology, 1999
- The Th1/Th2 paradigm and allergic disordersAllergy, 1998
- Priming of T cells by heat shock protein–peptide complexes as the basis of tumor vaccinesSeminars in Immunology, 1997
- Purification of Heat Shock Protein–Peptide Complexes for Use in Vaccination against Cancers and Intracellular PathogensMethods, 1997
- Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha.The Journal of Experimental Medicine, 1994
- T‐Cell Stimulation Induced by Idiotypes on Monoclonal Immunoglobulins in Patients with Monoclonal GammopathiesScandinavian Journal of Immunology, 1993
- Human TH1 and TH2 subsets: doubt no moreImmunology Today, 1991