期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 62, 期 8, 页码 1347-1357出版社
SPRINGER
DOI: 10.1007/s00262-013-1437-3
关键词
Cetuximab; VTX-2337; TLR8; ADCC; Head and neck cancer; Immunotherapy
资金
- NCI NIH HHS [P50 CA097190, R01 CA115902, P30 CA047904] Funding Source: Medline
- NIDCR NIH HHS [R01 DE019727, R01 DE19727] Funding Source: Medline
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, Fc gamma R-bearing cells. 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. Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8(+) T cells were isolated and analyzed using Cr-51 release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR(853-861) tetramer staining. 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 TNF alpha (p < 0.0001), IFN gamma (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. 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.
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