title: Opposing effects of toll-like receptor (TLR3) signaling in tumors can be therapeutically uncoupled to optimize the anticancer efficacy of TLR3 ligands.
abstract: Many cancer cells express Toll-like receptors (TLR) that offer possible therapeutic targets. Polyadenylic-polyuridylic acid [poly(A:U)] is an agonist of the Toll-like receptor TLR3 that displays anticancer properties. In this study, we illustrate how the immunostimulatory and immunosuppressive effects of this agent can be uncoupled to therapeutic advantage. We took advantage of two TLR3-expressing tumor models that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to type I IFN and poly(A:U), both in vitro and in vivo. Conventional chemotherapy or in vivo injection of poly(A:U), alone or in combination, failed to reduce tumor growth unless an immunochemotherapeutic regimen of vaccination against tumor antigens was included. CCL5 blockade improved the efficacy of immunochemotherapy, whereas CXCR3 blockade abolished its beneficial effects. These findings show how poly(A:U) can elicit production of a range of chemokines by tumor cells that reinforce immunostimulatory or immunosuppressive effects. Optimizing the anticancer effects of TLR3 agonists may require manipulating these chemokines or their receptors.
authors.affiliation: Institut Gustave Roussy, U848, 94805 Villejuif, France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Conforti
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ma
authors.forename: Yannis
authors.initials: Y
authors.lastname: Morel
authors.forename: Carine
authors.initials: C
authors.lastname: Paturel
authors.forename: Magali
authors.initials: M
authors.lastname: Terme
authors.forename: Sophie
authors.initials: S
authors.lastname: Viaud
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Maria
authors.initials: M
authors.lastname: Ferrantini
authors.forename: Ravindra
authors.initials: R
authors.lastname: Uppaluri
authors.forename: Robert
authors.initials: R
authors.lastname: Schreiber
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadière
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D011063:Poly A-U / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; C515188:Cxcr3 protein, mouse; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011063:Poly A-U