Template-Directed RIG-I Agonist Assembly for Targeted Cancer Immunotherapy

Abstract

Recent developments in the use of pattern recognition receptors (PRRs) aim to harness the innate power of the immune system for cancer therapy. Understanding how to recruit PRRs, such as RIG-I, in a tumor-selective manner is critical for its adoption in the clinic. We describe the use of a tumor-selective template-based agonist of RIG-I to induce type-I IFN signaling and tumor cell apoptosis. The agonist, termed ss-ppp-miRNA-21, comprises a single stranded RNA oligonucleotide modified with a 5-triphosphate and complementary to an endogenous miRNA enriched in tumor cells. We demonstrate the efficacy of the template-directed approach and detail mechanistic studies validating the hypothesis of a template-directed RIG-I agonist assembly using miRNA-21 as a target. The template-directed strategy described here moves us closer to making RIG-I a clinically relevant target in oncology because it achieves targeted activation of innate immunity in the tumor microenvironment in the context of systemic agonist injection.