title: A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma.
abstract: We studied the function of antitumor T and natural killer T (NKT) cells from the blood and tumor bed in 23 patients with premalignant gammopathy, nonprogressive myeloma, or progressive multiple myeloma. We show that antitumor killer T cells can be detected in patients with both progressive or nonprogressive myeloma. V alpha 24+V beta 11+ invariant NKT cells are detectable in the blood and tumor bed of all cohorts. However, freshly isolated NKT cells from both the blood and tumor bed of patients with progressive disease, but not nonprogressive myeloma or premalignant gammopathy, have a marked deficiency of ligand-dependent interferon-gamma production. This functional defect can be overcome in vitro using dendritic cells pulsed with the NKT ligand, alpha-galactosylceramide (alpha-GalCer). Fresh myeloma cells express CD1d, and can be efficiently killed by autologous NKT cells. We hypothesize that presentation of tumor derived glycolipids by myeloma cells leads to NKT dysfunction in vivo. These data demonstrate that clinical progression in patients with monoclonal gammopathies is associated with an acquired but potentially reversible defect in NKT cell function and support the possibility that these innate lymphocytes play a role in controlling the malignant growth of this incurable B cell tumor in patients.
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University, New York, NY 10021, USA. dhodapm@mail.rockefeller.edu
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Geller
authors.forename: David H
authors.initials: DH
authors.lastname: Chang
authors.forename: Kanako
authors.initials: K
authors.lastname: Shimizu
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Fujii
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Dhodapkar
authors.forename: Joseph
authors.initials: J
authors.lastname: Krasovsky
mesh_terms: D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d; D015415:Biomarkers; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D010265:Paraproteinemias / Q000276:immunology / Q000378:metabolism; D011230:Precancerous Conditions / Q000276:immunology* / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D015415:Biomarkers; C526877:CD1D protein, human; D015847:Interleukin-4; D007371:Interferon-gamma