Oncotarget

Research Papers:

Systemic administration of a TLR7 agonist attenuates regulatory T cells by dendritic cell modification and overcomes resistance to PD-L1 blockade therapy

Naoto Nishii, Hidetake Tachinami, Yuta Kondo, Yulong Xia, Yoshihisa Kashima, Tatsukuni Ohno, Shigenori Nagai, Lixin Li, Walter Lau, Hiroyuki Harada and Miyuki Azuma _

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Oncotarget. 2018; 9:13301-13312. https://doi.org/10.18632/oncotarget.24327

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Abstract

Naoto Nishii1,2, Hidetake Tachinami1, Yuta Kondo1, Yulong Xia1, Yoshihisa Kashima1,2, Tatsukuni Ohno1, Shigenori Nagai1, Lixin Li3, Walter Lau3, Hiroyuki Harada2 and Miyuki Azuma1

1Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

2Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

3Birdie Biopharmaceuticals Inc., Iselin, NJ, USA

Correspondence to:

Miyuki Azuma, email: miyuki.mim@tmd.ac.jp

Keywords: TLR7 agonist; resiquimod; immune checkpoint blockade; companion drug; regulatory T cells

Received: November 11, 2017     Accepted: January 19, 2018     Published: January 27, 2018

ABSTRACT

Research on immune checkpoint blockade therapy has made great progress in cancer immunotherapy, but the number of patients who benefit from this therapy remains limited. In this study, we examined the effects of monotherapy with systemic low-dose resiquimod, a synthesized TLR7 agonist, and examined its combined effects with PD-L1 blockade in two PD-L1 blockade-resistant tumor models (SCCVII and Colon 26). Resiquimod monotherapy in SCCVII tumors, representing impaired CD8+ T cell function and accelerated regulatory T cells (Tregs) within the tumors, efficiently reduced tumor growth with more recruitment of CD8+ T cells and a reduction of Treg. The results of resiquimod monotherapy in Colon 26, representing impaired Treg recruitment, were inferior to that in SCCVII. Combined resiquimod treatment with PD-L1 blockade exerted clear additional effects, as it was associated with reduced tumor size, attenuation of Tregs, and an increased ratio of CD8+ T cells/Tregs in both tumors. Systemic administration of low-dose resiquimod induced a transient and rapid activation of plasmacytoid and conventional dendritic cells, resulting in enhanced priming of T cells in regional lymph nodes. Experiments with more limited doses of resiquimod that did not yield beneficial effects after single treatment, showed additional effects to PD-L1 blockade and comparable antitumor effects when the frequency of anti-PD-L1 therapy was decreased. Our results suggest that systemic administration of low-dose resiquimod is useful as a companion drug to PD-1/PD-L1 blockade therapy.


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