title: TLR4 engagement during TLR3-induced proinflammatory signaling in dendritic cells promotes IL-10-mediated suppression of antitumor immunity.
abstract: Toll-like receptor (TLR) agonists are promising adjuvants for immune therapy of cancer, but their potential efficacy as single or combinatorial agents has yet to be fully evaluated. Here, we report that among all TLR agonists tested, dendritic cells (DC) stimulated with the TLR3 agonist polyI:C displayed the strongest activity in stimulating proinflammatory responses and the production of melanoma antigen-specific CD8(+) T cells. Simultaneous treatment with TLR7/8 agonists further improved these responses, but the inclusion of bacterial lipopolysaccharide (LPS), a TLR4 agonist, suppressed proinflammatory cytokine production. This inhibition was contingent upon rapid induction of the suppressive cytokine interleukin (IL)-10 by LPS, leading to dysregulated immune responses and it could be reversed by signal transducers and activators of transcription 3 knockdown, p38 blockade or antibodies to IL-10 and its receptor. Our findings show how certain TLR agonist combinations can enhance or limit DC responses associated with antitumor immunity, through their relative ability to induce IL-10 pathways that are immune suppressive.
authors: New York University Langone Medical Center Cancer Institute, New York, New York, USA.
authors: Dusan
authors: D
authors: Bogunovic
authors: Olivier
authors: O
authors: Manches
authors: Emmanuelle
authors: E
authors: Godefroy
authors: Alice
authors: A
authors: Yewdall
authors: Anne
authors: A
authors: Gallois
authors: Andres M
authors: AM
authors: Salazar
authors: Isabelle
authors: I
authors: Marie
authors: David E
authors: DE
authors: Levy
authors: Nina
authors: N
authors: Bhardwaj
mesh_terms: D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D016753:Interleukin-10