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Cancer Immunology, Immunotherapy

, Volume 64, Issue 10, pp 1229–1239 | Cite as

TLR7 tolerance is independent of the type I IFN pathway and leads to loss of anti-tumor efficacy in mice

  • Erina Koga-Yamakawa
  • Masashi Murata
  • Simon J. Dovedi
  • Robert W. Wilkinson
  • Yosuke Ota
  • Hiroki Umehara
  • Eiji Sugaru
  • Yuko Hirose
  • Hideyuki Harada
  • Philip J. Jewsbury
  • Setsuko Yamamoto
  • David T. Robinson
  • Chiang J. Li
Original Article

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.

Keywords

Toll-like receptor 7 Tolerance DSR-6434 TLR7 downregulation Cancer Immunotherapy 

Abbreviations

ANOVA

Analysis of variance

BM-pDC

Bone marrow-derived plasmacytoid dendritic cell

CPE

Cytopathic effect

DC

Dendritic cell

ELISA

Enzyme-linked immunosorbent assay

HBSS

Hank’s balanced salt solution

IFN

Interferon

IFN-α/β R KO

Interferon alpha/beta receptor knockout

IL-6

Interleukin-6

IRAK

Interleukin-1-receptor-associated kinase

IRF

Interferon-regulatory factor

i.v.

Intravenous administration

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

mRNA

Messenger RNA

MyD88

Myeloid differentiation primary response gene 88

NF-κB

Nuclear factor-kappa B

PAMP

Pathogen-associated molecular pattern

pDC

Plasmacytoid dendritic cell

SHIP

Src homology 2 domain-containing inositol polyphosphate phosphatase

SLE

Systemic lupus erythematosus

TAM pathway

Tyro3, Axl and Mer pathway

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor alpha

TRAF

Tumor necrosis factor-receptor-associated factor

Notes

Acknowledgments

The authors thank Yoshiaki Isobe, Hideo Takasu, Yasuo Kashiwazaki, Yutaka Ueda, Haruhisa Iguchi, Masashi Goto, Tomoaki Nakamura, Hirotaka Kurebayashi, Yukari Ishitsubo, Miki Takatsuka and Yoko Tsunashima (Sumitomo Dainippon pharma Cancer Institute or Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan) for their involvement in this study.

Conflict of interest

Erina Koga-Yamakawa, Masashi Murata, Yosuke Ota, Hiroki Umehara, Eiji Sugaru, Yuko Hirose, Hideyuki Harada and Setsuko Yamamoto are current employees of Sumitomo Dainippon Pharma Co., Ltd. Simon J. Dovedi, Robert W. Wilkinson, David T. Robinson and Philip J. Jewsbury are current or former employees and stockholders of AstraZeneca. Chiang J. Li is President, Chief Executive Officer and Chief Marketing Officer of Boston Biomedical, Inc, Head of Global Oncology for Sumitomo Dainippon Pharma Group.

Supplementary material

262_2015_1730_MOESM1_ESM.pdf (161 kb)
Supplementary material 1 (PDF 161 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Erina Koga-Yamakawa
    • 1
  • Masashi Murata
    • 1
  • Simon J. Dovedi
    • 2
    • 5
  • Robert W. Wilkinson
    • 2
    • 6
  • Yosuke Ota
    • 1
  • Hiroki Umehara
    • 1
    • 3
  • Eiji Sugaru
    • 1
  • Yuko Hirose
    • 1
  • Hideyuki Harada
    • 4
  • Philip J. Jewsbury
    • 2
  • Setsuko Yamamoto
    • 1
  • David T. Robinson
    • 2
  • Chiang J. Li
    • 3
  1. 1.Sumitomo Dainippon Pharma (DSP) Cancer InstituteSumitomo Dainippon PharmaOsakaJapan
  2. 2.Oncology Innovative Medicines and Early Development (iMed)AstraZenecaMacclesfieldUK
  3. 3.Boston Biomedical, Inc.CambridgeUSA
  4. 4.Drug Research DivisionSumitomo Dainippon PharmaSuitaJapan
  5. 5.Manchester Cancer Research Centre, Institute of Cancer SciencesUniversity of ManchesterManchesterUK
  6. 6.MedImmune LtdCambridgeUK

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