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J Exp Med. 2019 Dec 2;216(12):2854-2868. doi: 10.1084/jem.20190801. Epub 2019 Oct 10.

Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
2
Yale Center for Precision Cancer Modeling, Yale University School of Medicine, New Haven, CT.
3
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT.
4
Howard Hughes Medical Institute, Chevy Chase, MD.
5
Department of Molecular Biophysics and Biochemistry, W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT.
6
Department of Dermatology, Yale University School of Medicine, New Haven, CT.
7
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT anna.pyle@yale.edu.
8
Department of Chemistry, Yale University, New Haven, CT.
9
Department of Immunobiology, Yale University School of Medicine, New Haven, CT akiko.iwasaki@yale.edu.

Abstract

Cytosolic nucleic acid-sensing pathways can be triggered to enhance immune response to cancer. In this study, we tested the antitumor activity of a unique RIG-I agonist, stem loop RNA (SLR) 14. In the immunogenic tumor models, we observed significant tumor growth delay and an extended survival in SLR14-treated mice. SLR14 also greatly improved antitumor efficacy of anti-PD1 antibody over single-agent treatment. SLR14 was mainly taken up by CD11b+ myeloid cells in the tumor microenvironment, and many genes associated with immune defense were significantly up-regulated after treatment, accompanied by increase in the number of CD8+ T lymphocytes, NK cells, and CD11b+ cells in SLR14-treated tumors. Strikingly, SLR14 dramatically inhibited nonimmunogenic B16 tumor growth, and the cured mice developed an immune memory. Furthermore, a systemic antitumor response was observed in both bilateral and tumor metastasis models. Collectively, our results demonstrate that SLR14 is a promising therapeutic RIG-I agonist for cancer treatment, either alone or in combination with existing immunotherapies.

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