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Helms, M.W.* ; Jahn-Hofmann, K.* ; Gnerlich, F.* ; Metz-Weidmann, C.* ; Braun, M.* ; Dietert, G.* ; Scherer, P.* ; Grandien, K.* ; Theilhaber, J.* ; Cao, H.* ; Wagenaar, T.R.* ; Schnurr, M.M.* ; Endres, S. ; Wiederschain, D.* ; Scheidler, S.* ; Rothenfußer, S. ; Brunner, B.* ; König, L.M.*

Utility of the RIG-I agonist triphosphate RNA for melanoma therapy.

Mol. Cancer Ther. 18, 2343-2356 (2019)
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Open Access Green
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, FasK, 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 Cris 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Double-stranded-rna; 5'-triphosphate Rna; Checkpoint Blockade; Interferon-alpha; Cancer-therapy; Cutting Edge; T-cells; Activation; Il-10; Interleukin-10
ISSN (print) / ISBN 1535-7163
e-ISSN 1538-8514
Quellenangaben Band: 18, Heft: 12, Seiten: 2343-2356 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Unit for Clinical Pharmacology (KKG-EKLiP)
Förderungen Else Kroner-Fresenius-Stiftung
international doctoral program "i-Target: Immunotargeting of cancer" - the Elite Network of Bavaria
Deutsche Forschungsgemeinschaft