title: TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer.
abstract: The discovery of a targeted therapeutic compound along with its companion predictive biomarker is a major goal of clinical development for a personalized anticancer therapy to date. Here we present evidence of the predictive value of TLR3 expression by tumor cells for the efficacy of Poly (A:U) dsRNA in 194 breast cancer patients enrolled in a randomized clinical trial. Adjuvant treatment with double-stranded RNA (dsRNA) was associated with a significant decrease in the risk of metastatic relapse in TLR3 positive but not in TLR3-negative breast cancers. Moreover, we show the functional relevance of TLR3 expression by human tumor cells for the antitumor effects mediated by dsRNA in several preclinical mouse models carried out in immunocompromised animals. These 2 independent lines of evidence relied upon the generation of a novel tool, an anti-TLR3 antibody (40F9.6) validated for routine detection of TLR3 expression on paraffin-embedded tissues. Altogether, these data suggest that dsRNA mediates its therapeutic effect through TLR3 expressed on tumor cells, and could therefore represent an effective targeted treatment in patients with TLR3-positive cancers.
authors.affiliation: Translational Tumor Immunology Group, Ludwig Center for Cancer Research of the University of Lausanne, Lausanne, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Salaun
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Carine
authors.initials: C
authors.lastname: Asselin-Paturel
authors.forename: Yannis
authors.initials: Y
authors.lastname: Morel
authors.forename: Karine
authors.initials: K
authors.lastname: Chemin
authors.forename: Clarisse
authors.initials: C
authors.lastname: Dubois
authors.forename: Catherine
authors.initials: C
authors.lastname: Massacrier
authors.forename: Rosa
authors.initials: R
authors.lastname: Conforti
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Chenard
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.forename: Aicha
authors.initials: A
authors.lastname: Goubar
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
authors.forename: Michel
authors.initials: M
authors.lastname: Pierres
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Fabrice
authors.initials: F
authors.lastname: Andre
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D015337:Multicenter Studies as Topic; D012330:RNA, Double-Stranded / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D051196:Toll-Like Receptor 3 / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3