title: Peptide-loaded Langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo.
abstract: OBJECTIVE
  We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity.
  
  
  METHODS
  American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity.
  
  
  RESULTS
  Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-γ profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen-specific effector memory T cells (T(EMRA)) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity.
  
  
  CONCLUSIONS
  MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs.
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Romano
authors.forename: Marco
authors.initials: M
authors.lastname: Rossi
authors.forename: Gudrun
authors.initials: G
authors.lastname: Ratzinger
authors.forename: Maria-Angeles
authors.initials: MA
authors.lastname: de Cos
authors.forename: David J
authors.initials: DJ
authors.lastname: Chung
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchock
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004357:Drug Synergism; D004890:Erythema / Q000209:etiology; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D017252:CD3 Complex; D016827:CD8 Antigens; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D019409:Interleukin-15; D007376:Interleukin-2; D007371:Interferon-gamma