Antitumor monoclonal antibodies enhance cross-presentation ofcCellular antigens and the generation of myeloma-specific killer T cells by dendritic cells.
The mechanism of antitumor effect of monoclonal antibodies (mAbs) is not fully understood. Here we show that coating myeloma cells with anti-syndecan-1 antibody promotes cross-presentation of cellular antigens by dendritic cells (DCs) to autologous T cells from healthy donors. The tumor cells treated with anti-syndecan-1 or isotype-matched control antibody were fed to HLA-mismatched monocyte-derived immature DCs. Tumor cell-loaded mature DCs induced a strong CD8(+) T cell response that was specific for the cancer-testis (C-T) antigens expressed in the tumor. The CD8(+) T cells killed peptide-pulsed targets, as well as myeloma tumor cells. Importantly, mAbs-coated tumor-loaded DCs were consistently superior to DCs loaded with peptides or dying cells for eliciting tumor-specific killer T cells. This enhanced cross-presentation was not due to enhanced tumor cell uptake or to DC maturation. When mixtures of NY-Eso-1-positive and -negative myeloma cells were captured by DCs, the anti-syndecan-1 antibody had to be on the NY-Eso-1-positive cells to elicit NY-Eso-1-specific response. Cross-presentation was inhibited by pretreatment of DCs with Fc gamma receptor blocking antibodies. Targeting of mAb-coated tumors to DCs may contribute to the efficacy of tumor-reactive mAb and offers a new strategy for immunotherapy.
Dhodapkar
Kavita M
KM
Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University, New York, NY 10021, USA.
Krasovsky
Joseph
J
Williamson
Barbara
B
Dhodapkar
Madhav V
MV
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000276:immunology* / Q000494:pharmacology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008565:Membrane Proteins; D009101:Multiple Myeloma / Q000628:therapy*; D009363:Neoplasm Proteins / Q000276:immunology; D011506:Proteins / Q000276:immunology; D011509:Proteoglycans / Q000276:immunology; D017452:Receptors, IgG / Q000378:metabolism; D053667:Syndecans; D013601:T-Lymphocytes / Q000276:immunology*; D013736:Testicular Neoplasms / Q000276:immunology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; C072013:MAGEA3 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011509:Proteoglycans; D017452:Receptors, IgG; D053667:Syndecans; D007371:Interferon-gamma