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Cancer Res. 2018 Nov 1;78(21):6183-6195. doi: 10.1158/0008-5472.CAN-18-0730. Epub 2018 Sep 17.

Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers.

Author information

1
Cancer Biology Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee.
2
Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee.
3
Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
4
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
5
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut.
6
Howard Hughes Medical Institute, Chevy Chase, Maryland.
7
Department of Chemistry, Yale University, New Haven, Connecticut.
8
Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee.
9
Cancer Biology Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee. Rebecca.cook@vanderbilt.edu.

Abstract

Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/DDX58) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell-intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment in vivo Significance: These findings describe the first in vivo delivery of RIG-I mimetics to tumors, demonstrating a potent immunogenic and therapeutic effect in the context of otherwise poorly immunogenic breast cancers. Cancer Res; 78(21); 6183-95. ©2018 AACR.

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