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

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

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1874-1887
Number of pages14
JournalCell Reports
Volume19
Issue number9
DOIs
Publication statusPublished - 2017 May 30
Externally publishedYes

Keywords

  • PD-L1 blockade
  • Toll-like receptor 3
  • cancer immunotherapy
  • double-stranded RNA
  • innate immunity
  • priming adjuvant
  • tumor immunity
  • tumor-associated antigen
  • vaccine immunotherapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy'. Together they form a unique fingerprint.

Cite this