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http://purl.uniprot.org/citations/23685782http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23685782http://www.w3.org/2000/01/rdf-schema#comment"

Background

Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10-20 % of patients. An immunological mechanism of action such as natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells.

Objective

To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells.

Methods

Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8(+) T cells were isolated and analyzed using (51)Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR853-861 tetramer staining.

Results

TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFα (p < 0.0001), IFNγ (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co-cultures significantly increased DC priming of EGFR-specific CD8(+) T cells in the presence of cetuximab.

Discussion

VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.org/dc/terms/identifier"doi:10.1007/s00262-013-1437-3"xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/author"Ferris R.L."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/author"Lim C.M."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/author"Matthews M."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/author"Dietsch G."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/author"Hershberg R."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/author"Stephenson R.M."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/date"2013"xsd:gYear
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/name"Cancer Immunol Immunother"xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/pages"1347-1357"xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/title"TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells."xsd:string
http://purl.uniprot.org/citations/23685782http://purl.uniprot.org/core/volume"62"xsd:string
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