title: Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients.
abstract: OBJECTIVE
  Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8(+) CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging.
  
  
  METHODS
  FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)-specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-γ release assays and flow cytometry.
  
  
  RESULTS
  FcγRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR(853-861)-specific CD8(+) T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR(+) tumor cells and FcγRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ-dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (T(H)1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell-induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3.
  
  
  CONCLUSIONS
  Cetuximab-activated NK cells promote DC maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through "NK-DC cross-talk." FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response.
authors: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Raghvendra M
authors: RM
authors: Srivastava
authors: Steve C
authors: SC
authors: Lee
authors: Pedro A
authors: PA
authors: Andrade Filho
authors: Christopher A
authors: CA
authors: Lord
authors: Hyun-Bae
authors: HB
authors: Jie
authors: H Carter
authors: HC
authors: Davidson
authors: Andrés
authors: A
authors: López-Albaitero
authors: Sandra P
authors: SP
authors: Gibson
authors: William E
authors: WE
authors: Gooding
authors: Soldano
authors: S
authors: Ferrone
authors: Robert L
authors: RL
authors: Ferris
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D018920:Coculture Techniques; D045142:Cross-Priming / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D020239:Receptor Cross-Talk / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D016207:Cytokines; C496124:FCGR3A protein, human; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017452:Receptors, IgG; C073119:TAP1 protein, human; D007371:Interferon-gamma; D066246:ErbB Receptors; D000068818:Cetuximab