Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2.
Dendritic cells (DC) perform an important role in the initiation of the immune response through the local secretion of inflammatory mediators within diseased tissue in response to Toll-like receptor (TLR) ligation. However, DC vaccine strategies fail to make use of this capability against cancer. To harness the TLR response capability of DC against cancer, we tested a series of recombinant genes for their ability to redirect DC function specifically against a tumor-associated antigen. Each gene encoded a cell surface chimeric protein made up of extracellular single-chain immunoglobulin anti-erbB2 linked to an intracellular TLR-signaling component composed of either myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1 (IRAK-1) or the cytoplasmic domain of TLR4. Each gene was expressed in the DC line, JAWS II, to a similar degree following retroviral transduction. However, only the chimera containing IRAK-1 was able to mediate interleukin-12 and tumor necrosis factor-alpha secretion. Since TLR engagement can also activate DC and enhance their ability to stimulate T cells, we ligated the chimeric anti-erbB2-IRAK-1 receptor and determined the effect on the stimulation of T cells. We found that JAWS II cells triggered through chimeric anti-erbB2-IRAK-1 displayed an enhanced ability to stimulate ovalbumin-specific OT-II CD4(+) T cells. This first description of the generation of tumor-reactive DC may lead to the development of new cell-based vaccines that can act at both the tumor site to induce danger and at the lymph node to stimulate a specific T-cell response.
Xu
Y
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Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Vic. 3002, Australia.
Darcy
P K
PK
Kershaw
M H
MH
D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D051193:Toll-Like Receptors / Q000378:metabolism*
D053592:Interleukin-1 Receptor-Associated Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D051193:Toll-Like Receptors; C508053:ERBB2 protein, human; C507769:Irak1 protein, mouse