title: Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2.
abstract: 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.
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Vic. 3002, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: P K
authors.initials: PK
authors.lastname: Darcy
authors.forename: M H
authors.initials: MH
authors.lastname: Kershaw
mesh_terms: 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*
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D051193:Toll-Like Receptors; C508053:ERBB2 protein, human; C507769:Irak1 protein, mouse