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A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy.
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Title: | A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy. |
Authors: | Takeda, Yohei Browse this author | Kataoka, Keisuke Browse this author | Yamagishi, Junya Browse this author →KAKEN DB | Ogawa, Seishi Browse this author | Seya, Tsukasa Browse this author →KAKEN DB | Matsumoto, Misako Browse this author →KAKEN DB |
Keywords: | cancer immunotherapy | double-stranded RNA | innate immunity | PD-L1 blockade | priming adjuvant | Toll-like receptor 3 | tumor-associated antigen | tumor immunity | vaccine immunotherapy |
Issue Date: | 30-May-2017 |
Publisher: | Elsevier |
Journal Title: | Cell Reports |
Volume: | 19 |
Issue: | 9 |
Start Page: | 1874 |
End Page: | 1887 |
Publisher DOI: | 10.1016/j.celrep.2017.05.015 |
PMID: | 28564605 |
Abstract: | 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-β 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. |
Rights: | http://creativecommons.org/licenses/by/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/70698 |
Appears in Collections: | 国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 山岸 潤也
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