Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment

David L. Elion and Rebecca S. Cook _

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Oncotarget. 2018; 9:29007-29017. https://doi.org/10.18632/oncotarget.25626

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David L. Elion1 and Rebecca S. Cook2,3,4

1Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

2Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

3Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA

4Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA

Correspondence to:

Rebecca S. Cook, email: [email protected]

Keywords: immunotherapy; RIG-I; innate immunity; pyroptosis; tumor microenvironment

Received: March 24, 2018     Accepted: May 24, 2018     Published: June 22, 2018


Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum. Approaches aimed at intrinsic cellular immunity in the tumor microenvironment are less understood, but are of intense interest, based on their ability to induce tumor cell apoptosis while orchestrating innate and adaptive immune responses against tumor antigens. The intrinsic immune response is initiated by ancient, highly conserved intracellular proteins that detect viral infection. For example, the RIG-I-like receptors (RLRs), a family of related RNA helicases, detect viral oligonucleotide patterns of certain RNA viruses. RLR activation induces immunogenic cell death of virally infected cells, accompanied by increased inflammatory cytokine production, antigen presentation, and antigen-directed immunity against virus antigens. Approaches aimed at non-infectious RIG-I activation in cancers are being tested as a treatment option, with the goal of inducing immunogenic tumor cell death, stimulating production of pro-inflammatory cytokines, enhancing tumor neoantigen presentation, and potently increasing cytotoxic activity of tumor infiltrating lymphocytes. These studies are finding success in several pre-clinical models, and are entering early phases of clinical trial. Here, we review pre-clinical studies of RLR agonists, including the successes and challenges currently faced RLR agonists on the path to clinical translation.

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