title: TLR3-Induced Maturation of Murine Dendritic Cells Regulates CTL Responses by Modulating PD-L1 Trafficking.
abstract: Targeting TLR3 through formulations of polyI:C is widely studied as an adjuvant in cancer immunotherapy. The efficacy of such targeting has been shown to increase in combination with anti-PD-L1 treatment. Nevertheless, the mechanistic details of the effect of polyI:C on DC maturation and the impact on T-DC interactions upon PD-L1 blockade is largely unknown. Here we found that although DC treatment with polyI:C induced a potent inflammatory response including the production of type I interferon, polyI:C treatment of DCs impaired activation of peptide specific CD8+ T cells mainly due to PD-L1. Interestingly, we found that PD-L1 trafficking to the cell surface is regulated in two waves in polyI:C-treated DCs. One induced upon overnight treatment and a second more rapid one, specific to polyI:C treatment, was induced upon CD40 signaling leading to a further increase in surface PD-L1 in DCs. The polyI:C-induced cell surface PD-L1 reduced the times of contact between DCs and T cells, potentially accounting for limited T cell activation. Our results reveal a novel CD40-dependent regulation of PD-L1 trafficking induced upon TLR3 signaling that dictates its inhibitory activity. These results provide a mechanistic framework to understand the efficacy of anti-PD-L1 cancer immunotherapy combined with TLR agonists.
authors.affiliation: Institut Curie, PSL Research University, INSERM, U 932, Paris, France.
authors.forename: Aditi
authors.initials: A
authors.lastname: Varthaman
authors.affiliation: Institut Curie, PSL Research University, INSERM, U 932, Paris, France.
authors.forename: Hélène D
authors.initials: HD
authors.lastname: Moreau
authors.affiliation: Institut Curie, PSL Research University, INSERM, U 932, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Maurin
authors.affiliation: Institut Curie, PSL Research University, INSERM, U 932, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Benaroch
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011070:Poly I-C / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; D019013:CD40 Antigens; C498919:Cd274 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C