title: Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1.
abstract: Human CD34(+) progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-α mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-α/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1(+) leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors.
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Romano
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Cotari
authors.forename: Rosa
authors.initials: R
authors.lastname: Barreira da Silva
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.forename: David J
authors.initials: DJ
authors.lastname: Chung
authors.forename: Francesca
authors.initials: F
authors.lastname: Avogadri
authors.forename: Mitsu J
authors.initials: MJ
authors.lastname: Fink
authors.forename: Erin T
authors.initials: ET
authors.lastname: St Angelo
authors.forename: Babak
authors.initials: B
authors.lastname: Mehrara
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.forename: Gregoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D017951:Antigen Presentation; D001752:Blast Crisis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007801:Langerhans Cells / Q000276:immunology* / Q000473:pathology; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; C569274:IL15 protein, human; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D050799:STAT5 Transcription Factor; D025721:WT1 Proteins