Abstract
The innate immune system provides the first line of defense against pathogen infection though also influences pathways involved in cancer immunosurveillance. The innate immune system relies on a limited set of germ line-encoded sensors termed pattern recognition receptors (PRRs), signaling proteins and immune response factors. Cytosolic receptors mediate recognition of danger damage-associated molecular patterns (DAMPs) signals. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Recent studies revealed that PRRs respond to nucleic acids (NA) released by dying, damaged, cancer cells, as danger DAMPs signals, and presence of signaling proteins across cancer types suggests that these signaling mechanisms may be involved in cancer biology. DAMPs play important roles in shaping adaptive immune responses through the activation of innate immune cells and immunological response to danger DAMPs signals is crucial for the host response to cancer and tumor rejection. Furthermore, PRRs mediate the response to NA in several vaccination strategies, including DNA immunization. As route of double-strand DNA intracellular entry, DNA immunization leads to expression of key components of cytosolic NA-sensing pathways. The involvement of NA-sensing mechanisms in the antitumor response makes these pathways attractive drug targets. Natural and synthetic agonists of NA-sensing pathways can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment and are being explored as promising adjuvants in cancer immunotherapies. In this minireview, we discuss how cGAS–STING and RIG-I–MAVS pathways have been targeted for cancer treatment in preclinical translational researches. In addition, we present a targeted selection of recent clinical trials employing agonists of cytosolic NA-sensing pathways showing how these pathways are currently being targeted for clinical application in oncology.
Highlights
The innate immune system provides the first line of defense against pathogen infection
A phosphorylation cascade allows signal transmission leading to activation of interferon regulatory factor (IRF) 3 and nuclear factor κB (NF-κB) that translocate into the nucleus to drive transcription of type-I interferons (IFNs), interferon-stimulated genes (ISGs), proinflammatory cytokines and chemokines [5, 6]
The spatiotemporal orchestration of innate stimulation with antigen cross-presentation in APCs represents a crucial challenge in reaching a strong tumor specific T-cell response, which in turn is crucial for cancer immunotherapy
Summary
The innate immune system provides the first line of defense against pathogen infection. Recent studies revealed that damaged NAs released by dying cancer cells can be sensed as DAMP danger signals by PRRs present on CD8α dendritic cells (DCs) in tumor microenvironment (TME), leading to activation of cGAS-STING and/or RIG-I/ MDA5 signaling pathways. Activation of cytosolic DNA sensing pathways impacts on autophagy and tumor antigens (Ags) cross-presentation in DCs. Type-I IFNs production by DCs represents the link between NAs sensing and effective Ags cross-presentation to CD8+ T cells, linking innate and adaptive immunity [14].
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