Abstract
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.
Highlights
The immune system is capable of targeted tumor cell killing through the process of immunosurveillance
It is thought that immune checkpoint inhibitors (ICI) may be less effective in tumors that are poorly immunogenic, as defined by low levels of tumor infiltrating lymphocytes (TILs), minimal cross-presentation of tumor neoantigens, and high levels of immune suppressive leukocytes such as regulatory T-cells (TRegs), tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) [4,5,6,7]
Since a ‘T-cell inflamed’ microenvironment is often associated with an improved prognosis for several cancers, and correlates with increased tumor sensitivity to ICIs, the pro-inflammatory phenotype induced by RIG-I activation may be an attractive treatment approach to increase tumor immunogenicity and clinical success of ICIs
Summary
The immune system is capable of targeted tumor cell killing through the process of immunosurveillance. RLR activation induces immunogenic cell death of virally infected cells, accompanied by increased inflammatory cytokine production, antigen presentation, and antigendirected immunity against virus antigens.
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