Abstract
Simple SummaryOur cells can recognize DNA or RNA from pathogens, such as viruses. The proteins that recognize these nucleic acids are known as nucleic acid sensors. Upon activation, they trigger immune responses that result in the elimination of the infected cells. Recent research has shown how we can mimic this process in cancer and recruit immune cells against the tumor. Among the different cell types within a tumor, endothelial cells that line the blood vessels play a main role as conduits for nutrients and oxygen and highways for the immune cells. In this review, we discuss two different nucleic acid sensors—the three-prime repair exonuclease 1 (TREX1) and the retinoic acid-inducible gene 1 (RIG-I)—and how they play a role in endothelial cells. We present some approaches to target these pathways within the cancer blood vessels to disrupt the blood supply and attract immune responses to cancers.Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors, such as cGAS-STING, in combination with immunotherapies. In this review, we present a case for targeting nucleic acid-sensing pathways within the tumor vasculature to invigorate tumor-immune responses. We introduce two specific nucleic acid sensors—the DNA sensor TREX1 and the RNA sensor RIG-I—and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid-sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment by co-opting both vascular and immune cell types.
Highlights
Cancers 2021, 13, 4452 Cancers 2021, 13, x response
These findings suggest that three-prime repair exonuclease 1 (TREX1) and other enzymes with nuclease activity play an important role in the context of the cGAS-STING signaling pathway’s regulation of inflammation in tissues
TREX1 is phosphorylated during mitosis, which disrupts its interactions with the OST complex without affecting its DNAse activity [20]
Summary
DNAse III, or TREX1, is an exonuclease that degrades exogenous DNA. TREX1 is a member of the DnaQ family of 3 → 5 exonucleases. Apoptotic self-DNA accumulates in these macrophages and triggers type I interferon responses This phenotype is rescued by the loss of STING, as cytosolic DNA was unable to trigger inflammatory cytokine production in the STING−/− DNAse II−/− double knockout mice [23]. Coquel et al [28] discovered that the dNTPase SAMHD1 promotes the degradation of nascent DNA at stalled replication forks This function appears to co-opt the exonuclease activity of MRE11, thereby activating the ATR–CHK1 checkpoint and enabling the cells to recover and restart the stalled replication forks. The depletion of SAMHD1 led to an increase in the accumulation of ssDNA fragments in the cytosol and the subsequent activation of the cGAS–STING pathway These findings suggest that TREX1 and other enzymes with nuclease activity play an important role in the context of the cGAS-STING signaling pathway’s regulation of inflammation in tissues
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