title: TLR7 tolerance is independent of the type I IFN pathway and leads to loss of anti-tumor efficacy in mice.
abstract: Systemic administration of small molecule toll-like receptor (TLR)-7 agonists leads to potent activation of innate immunity and to the generation of anti-tumor immune responses. However, activation of TLRs with small molecule agonists may lead to the induction of TLR tolerance, defined as a state of hyporesponsiveness to subsequent agonism, which may limit immune activation, the generation of anti-tumor responses and clinical response. Our data reveal that dose scheduling impacts on the efficacy of systemic therapy with the selective TLR7 agonist, 6-amino-2-(butylamino)-9-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (DSR-6434). In a preclinical model of renal cell cancer, systemic administration of DSR-6434 dosed once weekly resulted in a significant anti-tumor response. However, twice weekly dosing of DSR-6434 led to the induction of TLR tolerance, and no anti-tumor response was observed. We show that TLR7 tolerance was independent of type I interferon (IFN) negative feedback because induction of TLR7 tolerance was also observed in IFN-α/β receptor knockout mice treated with DSR-6434. Moreover, our data demonstrate that treatment of bone marrow-derived plasmacytoid dendritic cells (BM-pDC) with DSR-6434 led to downregulation of TLR7 expression. From our data, dose scheduling of systemically administered TLR7 agonists can impact on anti-tumor activity through the induction of TLR tolerance. Furthermore, TLR7 expression on pDC may be a useful biomarker of TLR7 tolerance and aid in the optimization of dosing schedules involving systemically administered TLR7 agonists.
authors.affiliation: Sumitomo Dainippon Pharma (DSP) Cancer Institute, Sumitomo Dainippon Pharma, 3-1-98, Kasugade Naka, Konohana-ku, Osaka, 554-0022, Japan, erina-koga@ds-pharma.co.jp.
authors.forename: Erina
authors.initials: E
authors.lastname: Koga-Yamakawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Murata
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.forename: Hiroki
authors.initials: H
authors.lastname: Umehara
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugaru
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hirose
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Harada
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Jewsbury
authors.forename: Setsuko
authors.initials: S
authors.lastname: Yamamoto
authors.forename: David T
authors.initials: DT
authors.lastname: Robinson
authors.forename: Chiang J
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D045744:Cell Line, Tumor; D002985:Clinical Protocols; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C581841:DSR-6434; D007370:Interferon Type I; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000225:Adenine