Intratumoral delivery of RIG-I agonist induces robust anti-tumor immune responses

Abstract

Abstract Recent studies have revealed that cytosolic nucleic acid-sensing pathways such as cGAS-STING and RIG-I-MAVS are involved in cancer biology. How to employ agents or agonists of these pathways to develop new approaches for cancer treatment is a promising direction. In this study, we synthesized a unique, binding-specific RIG-I agonist called Stem Loop RNA (SLR) 14 and evaluated its in vivo anti-tumor efficacy. When tumor volume reached 40–80 mm3, SLR14 was delivered intratumorally, every 2–3 days, for a total of 5–6 doses. Our results show that, after SLR14 treatment, B16 melanoma growth was dramatically blocked and the mice displayed long-term survival. We also observed a significant increase of tumor-infiltrating lymphocytes, and demonstrated that anti-tumor efficacy of SLR14 was T cell-dependent using RAG−/− mice and T cell depletion. Next, we tested anti-tumor efficacy of SLR14 in the mice with immunogenic tumor --YUMMER1.7 (melanoma) or MC38 (colon cancer). Similarly, we also observed a significant delay of tumor growth and extended mouse survival. Moreover, combination treatment with SLR14 and anti-PD1 in these mice led to more remarkable antitumor effects than single treatment. Lastly, we found that SLR14 was mainly taken up by CD45+CD11b+ leukocytes including neutrophils and myeloid cells, suggesting that anti-tumor efficacy of SLR14 is initiated through activation of the RIG-I pathway in innate cells within the tumor microenvironment. Taken together, our data demonstrate that synthetic RIG-I agonist SLR14 is a promising therapeutic agent for a broad spectrum of tumor subtypes. A better understanding of nucleic-acid sensing mechanisms within the tumor microenvironment may yield novel approaches for cancer immunotherapy.