Abstract
The pattern recognition receptor RIG-I plays an important role in the recognition of nonself RNA and antiviral immunity. RIG-I's natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. In this study, we present comprehensive data validating the concept and utility of treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Using mRNA expression data of human tumors, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Furthermore, we confirm susceptibility of cancer cells to ppp-RNA treatment in different cellular models of human melanoma, revealing unexpected heterogeneity between cell lines in their susceptibility to RNA agonist features, including sequence, secondary structures, and presence of triphosphate. Cellular responses to RNA treatment (induction of type I IFN, FasR, MHC-I, and cytotoxicity) were demonstrated to be RIG-I dependent using KO cells. Following ppp-RNA treatment of a mouse melanoma model, we observed significant local and systemic antitumor effects and survival benefits. These were associated with type I IFN response, tumor cell apoptosis, and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen-specific CTLs following treatment with RIG-I agonists. Despite potential challenges in the generation and formulation of potent RIG-I agonists, ppp-RNA or analogues thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy.
Highlights
In recent years, immunotherapy has established itself as an important addition to the current armamentarium of cancer treatments, with a prominent role for immune checkpoint inhibitors [1, 2]
We were able to demonstrate that, within the melanomas contained in the the Cancer Genome Atlas (TCGA) data collection, there was an overall correlation of intratumoral RIG-I levels and the number of infiltrating immune cells as indicated by specific immune cell–associated expression signatures
While previously published data suggested a protective role for RIG-I in liver cancer [34, 35], we focused on the immunologic implications of RIG-I expression levels in human cancers with a focus on melanoma as a possible entry indication for treatment via intratumoral drug administration
Summary
Immunotherapy has established itself as an important addition to the current armamentarium of cancer treatments, with a prominent role for immune checkpoint inhibitors [1, 2]. Tumor biology has again proven to be complex and elusive, leaving a large portion of tumors unresponsive to currently available therapeutic options, in the absence of tumor-infiltrating immune cells susceptible for activation [3, 4]. New immune targets are emerging, with the group of. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Gnerlich: AstraZeneca, Innovative Medicines & Early Development Biotech Unit, Gothenburg, Sweden
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