Cell Reports
Volume 19, Issue 9, 30 May 2017, Pages 1874-1887
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2017.05.015Get rights and content
Under a Creative Commons license
open access

Highlights

  • Vaccine immunotherapy with ARNAX and tumor antigen overcomes anti-PD-L1 resistance

  • ARNAX induces anti-tumor CTLs and their infiltration into the tumor site via TLR3

  • ARNAX therapy establishes Th1-type anti-tumor immunity and leads to tumor regression

  • ARNAX therapy enhances anti-tumor responses in conjunction with PD-L1 blockade

Summary

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.

Keywords

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

Cited by (0)

4

These authors contributed equally

5

Lead Contact