Targeting TLR3 with no RIG-I/MDA5 activation is effective in immunotherapy for cancer

Introduction: Many forms of RNA duplexes with agonistic activity for pattern-recognition receptors have been reported, some of which are candidates for adjuvant immunotherapy for cancer. These RNA duplexes induce cytokines, interferons (IFNs) and cellular effectors mainly via two distinct pathways, TLR3/TICAM-1 and MDA5/MAVS. Areas covered: We determined which pathway of innate immunity predominantly participates in evoking tumor immunity in response to RNA adjuvants. Expert opinion: In knockout (KO) mouse studies, robust cytokine or IFN production is dependent on systemic activation of the MAVS pathway, whereas maturation of dendritic cells (DCs) to drive cellular effectors (i.e., NK and CTL) depends on the TICAM-1 pathway in DCs. MAVS activation often causes endotoxin-like cytokinemia, while the TICAM-1 activation does not. Unlike the TLR/MyD88 pathway, this TICAM-1 pathway barely accelerates tumor progression. Although the therapeutic effect in human patients of MAVS-activating or TICAM-1-activating RNA duplexes remains undetermined, the design of a TLR3 agonist with optimized toxicity and dose is an important goal for human immunotherapy. Here we summarize current knowledge on available RNA duplex formulations, and offer a possible approach to developing a promising RNA duplex for clinical tests.