論文

査読有り
2017年5月

A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

CELL REPORTS
  • Yohei Takeda
  • ,
  • Keisuke Kataoka
  • ,
  • Junya Yamagishi
  • ,
  • Seishi Ogawa
  • ,
  • Tsukasa Seya
  • ,
  • Misako Matsumoto

19
9
開始ページ
1874
終了ページ
1887
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.celrep.2017.05.015
出版者・発行元
CELL PRESS

Cancer patients having anti-programmed cell death-1 (PD-1)/PD ligand 1 (L1)-unresponsive tumors may benefit from advanced immunotherapy. Double-stranded RNA triggers dendritic cell (DC) maturation to cross-prime antigen-specific cytotoxic T lymphocytes (CTLs) via Toll-like receptor 3 (TLR3). The TLR3-specific RNA agonist, ARNAX, can induce anti-tumor CTLs without systemic cytokine/interferon (IFN) production. Here, we have developed a safe vaccine adjuvant for cancer that effectively implements anti-PD-L1 therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with anti-PD-L1 antibody, activated tumor-specific CTLs in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. The TLR3-TICAM-1-interferon regulatory factor (IRF) 3-IFN-beta axis in DCs exclusively participated in CD8(+) T cell cross-priming. ARNAX therapy established Th1 immunity in the tumor microenvironment, upregulating genes involved in DC/T cell/natural killer (NK) cell recruitment and functionality. Human ex vivo studies disclosed that ARNAX+ antigen induced antigen-specific CTL priming and proliferation in peripheral blood mononuclear cells (PBMCs), supporting the feasibility of ARNAX for potentiating anti-PD-1/PD-L1 therapy in human vaccine immunotherapy.

Web of Science ® 被引用回数 : 47

リンク情報
DOI
https://doi.org/10.1016/j.celrep.2017.05.015
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000402271100012&DestApp=WOS_CPL
URL
http://orcid.org/0000-0002-8263-9902

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