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Immunostimulatory RNA Oligonucleotides Induce an Effective Antitumoral NK Cell Response through the TLR7¹

Carole Bourquin,^23* Laura Schmidt,^2* Anna-Lisa Lanz,^* Bettina Storch,^* Cornelia Wurzenberger,^* David Anz,^* Nadja Sandholzer,^* Ralph Mocikat, Michael Berger,^* Hendrik Poeck,^* Gunther Hartmann, Veit Hornung, and Stefan Endres^*

^*Center for Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine and Dr. von Haunersches Kinderspital, Department of Pediatric Surgery, Ludwig-Maximilian University of Munich, Munich, Germany; Helmholtz Zentrum München, Institute of Molecular Immunology, Munich, Germany; and Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, Bonn, Germany

RNA oligonucleotides containing immune-activating sequences promote the development of cytotoxic T cell and B cell responses to Ag. In this study, we show for the first time that immunostimulatory RNA oligonucleotides induce a NK cell response that prevents growth of NK-sensitive tumors. Treatment of mice with immunostimulatory RNA oligonucleotides activates NK cells in a sequence-dependent manner, leading to enhanced IFN- production and increased cytotoxicity. Use of gene-deficient mice showed that NK activation is entirely TLR7-dependent. We further demonstrate that NK activation is indirectly induced through IL-12 and type I IFN production by dendritic cells. Reconstitution of TLR7-deficient mice with wild-type dendritic cells restores NK activation upon treatment with immunostimulatory RNA oligonucleotides. Thus, by activating both NK cells and CTLs, RNA oligonucleotides stimulate two major cellular effectors of antitumor immunity. This dual activation may enhance the efficacy of immunotherapeutic strategies against cancer by preventing the development of tumor immune escape variants.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft En 169/7-2 and Graduiertenkolleg 1202 to C.B. and S.E.), the excellence cluster CIPSM 114 (to S.E.) and the SFB-TR 36 (to S.E.), the LMUexcellent (research professorship to S.E.), the Else-Kröner Fresenius Foundation, and the BayImmuNet (to C.B. and S.E.). This work is part of the doctoral thesis of L.S. and A.L.L. supported by Graduiertenkolleg 1202.

² C.B. and L.S. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Carole Bourquin, Division of Clinical Pharmacology, University of Munich, Ziemsenstrasse 1, 80336 Munich, Germany. E-mail address: carole.bourquin{at}med.lmu.de

⁴ Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene I; DC, dendritic cell; DOTAP, N-[1-(2,3-dioleoxy)propyl]-N,N,N-trimethylammonium methylsulfate; MDA-5, melanoma differentiation-associated gene 5; PD, phosphodiester; PTO, phosphorothioate; β₂m, β₂-microglobulin; wt, wild type; BMDC, bone marrow-derived DC.