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+ Tcell 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 exvivo 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.
Highlights
ARNAX appears to escape from recognition by the RNA sensors, RIG-I and MDA5, and the DNA sensor, TLR9
Accumulating evidence suggests that type I IFN-signaling is critical for cross-priming in dendritic cell (DC) (Fuertes et al, 2011, 2013; Pantel et al, 2014)
Intratumoral mRNA expression of Gzmb, Ifng, Prf1, and Cxcl9 was upregulated by ARNAX+OVA and combination therapy (Figure 4E). These results collectively suggest that ARNAX serves as a priming adjuvant to induce Ag-specific CD8+ T cells in lymphoid tissues, and blockage of the programmed cell death-1 (PD-1)/PD-ligand 1 (L1) pathway augments ARNAX-mediated CD8+ T cell activation and infiltration into the tumor site, where cytotoxic T lymphocytes (CTLs) function is restored
Summary
Blockade of the programmed cell death-1 (PD-1) immune checkpoint pathway induces efficient remission in patients with metastatic cancers (Kamphorst and Ahmed, 2013; Hamid et al, 2013; Herbst et al, 2014; Tumeh et al, 2014), but responses are observed in only $20% of patients with all solid tumor types (Herbst et al, 2014; Tumeh et al, 2014). Preexistence of anti-tumor cytotoxic T lymphocytes (CTLs) and their infiltration into tumors are a prerequisite for treatment efficacy (Tumeh et al, 2014). The frequency of high nonsynonymous mutations in tumors is correlated with the efficacy of PD-1/PD-ligand-1 (PD-L1) blockade therapy and long-term survival of patients (Rizvi et al, 2015; Schumacher and Schreiber, 2015). Mutated tumor-associated antigens (TAAs) may be involved in the generation of anti-tumor CTLs and responses to PD-1/ PD-L1 blockade therapy. Tumor-specific CTLs have been characterized using TAA peptides and tetramers in peptide vaccine therapy preceding PD-1 checkpoint inhibition (Coulie et al, 2014). In patients responding to peptide vaccine therapy, tetramer-positive CTLs are increased in the blood and tumor sites. Insufficient induction of tumor-specific CTLs would have been a barrier to establishment of the vaccine therapy
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