title: Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by anti-CD40 immunotherapy.
abstract: Topical application of tumors with the TLR7 agonist imiquimod is an effective adjunct treatment for a range of primary dermatological cancers. However, for therapy to be effective against a broad range of solid tumor types, it must promote a strong systemic antitumor response that targets metastases in addition to primary tumor. We therefore investigated the potential of locally delivered imiquimod to stimulate an effective systemic antitumor response in a murine model of malignant mesothelioma (AB1-HA) with primary and distal tumors (dual tumor). Persistent delivery of imiquimod into primary tumor significantly retarded tumor growth in all treated mice compared with vehicle control. This local antitumor immune response required both CD8 T cells and NK cells, but not CD4 T cells, and was reliant on type I IFN induction. In vivo CTL studies and Ly6A/E staining of lymphocytes suggested that local imiquimod treatment had indeed induced a systemic, Ag-specific CD8 response. However, notably this response was not sufficient to retard the growth of an untreated distal tumor. Because local imiquimod treatment did not induce significant CD4 T cell responses, we investigated the efficacy of combining imiquimod with agonistic CD40 Ab (as a surrogate for CD4 T cell help). Combination of locally delivered imiquimod with systemic anti-CD40 immunotherapy not only significantly enhanced the local antitumor response, with 30% complete resolution, but it was also effective at significantly retarding growth of distal tumor. These results demonstrate that antitumor responses induced by locally delivered TLR7 agonists can be harnessed systemically for treating distal tumor.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Broomfield
authors.forename: Robbert G
authors.initials: RG
authors.lastname: van der Most
authors.forename: Amy C
authors.initials: AC
authors.lastname: Prosser
authors.forename: Sathish
authors.initials: S
authors.lastname: Mahendran
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tovey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Bruce W S
authors.initials: BW
authors.lastname: Robinson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Currie
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004359:Drug Therapy, Combination; D005260:Female; D000077271:Imiquimod; D007370:Interferon Type I / Q000008:administration & dosage; D007371:Interferon-gamma / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism / Q000627:therapeutic use; D008654:Mesothelioma / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007370:Interferon Type I; D008024:Ligands; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007371:Interferon-gamma; D000077271:Imiquimod