Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

Bourquin, Carole; Pommier, Aurélien; Hotz, Christian

doi:10.1016/j.phrs.2019.03.001

Cited by 47 publications

(40 citation statements)

References 61 publications

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“…As immune system antigens, exogenously purified circRNAs may mediate the activation of innate immunity by activating the retinoic acid-inducible gene I (RIG-I)-mediated pathway in vitro [65]. CircRNAinduced nucleic acid sensor RIG-I is a well-known innate immunity regulator [66,67], and RIG-I agonists have been shown to activate anticancer immune responses to fight tumours [68,69]. Therefore, exogenous circRNAs entering tumour cells have the potential to affect RIG-I and activate antitumour immunity (Fig.…”

Section: Circrnas Mediate Tumour Immune Surveillancementioning

confidence: 99%

Roles of circRNAs in the tumour microenvironment

et al. 2020

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The tumour microenvironment (TME) constitutes the area surrounding the tumour during its development and has been demonstrated to play roles in cancer-related diseases through crosstalk with tumour cells. Circular RNAs (circRNAs) are a subpopulation of endogenous noncoding RNAs (ncRNAs) that are ubiquitously expressed in eukaryotes and have multiple biological functions in the regulation of cancer onset and progression. An increasing number of studies have shown that circRNAs participate in the multifaceted biological regulation of the TME. However, details on the mechanisms involved have remained elusive until now. In this review, we analyse the effects of circRNAs on the TME from various perspectives, including immune surveillance, angiogenesis, hypoxia, matrix remodelling, exo-circRNAs and chemoradiation resistance. Currently, the enormous potential for circRNA use in targeted therapy and as noninvasive biomarkers have drawn our attention. We emphasize the prospect of targeting circRNAs as an essential strategy to regulate TME, overcome cancer resistance and improve therapeutic outcomes.

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Section: Circrnas Mediate Tumour Immune Surveillancementioning

confidence: 99%

Roles of circRNAs in the tumour microenvironment

et al. 2020

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“…DN052 is a novel TLR8 agonist displaying differentiated profiles compared to motolimod in that DN052 is more selective for TLR8 while sparing TLR7. Several TLR agonists including TLR4, 7, TLR7/8 dual and TLR9 agonists can be used mainly as a topical drug or dosed locally such as intratumoral injection because they are too toxic if used systemically [5]. This has been a major hurdle which limits their application in the clinic [12,31,32].…”

Section: Discussionmentioning

confidence: 99%

“…Most of the targets drugged by the recently approved cancer immunotherapeutic agents including the immune checkpoint proteins PD-1, PD-L1 and CTLA-4 function in adaptive immune pathways [2,3]. In contrast, targets involved in the innate immune pathway had been under-developed [4,5]. Innate immunity acts as the body's first line of immune defense.…”

Section: Introductionmentioning

confidence: 99%

Development of a novel TLR8 agonist for cancer immunotherapy

Wang¹,

Yang²,

Li³

et al. 2020

Mol Biomed

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Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase 1 clinical trials.

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“…Intriguingly, STING activation can be triggered pharmacologically by synthetic small molecules and engineered macromolecules (12). This represents a potentially formidable strategy for eliciting broad-spectrum antiviral activity (13), generating anti-tumor immunity (14), and enhancing vaccine immunogenicity (15). In light of this, numerous efforts are underway to discover novel and safe STING-based immunomodulators that can be utilized for potentiating desirable clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner

et al. 2020

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The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells in ex vivo assays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule.

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Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

Cited by 47 publications

References 61 publications

Roles of circRNAs in the tumour microenvironment

Roles of circRNAs in the tumour microenvironment

Development of a novel TLR8 agonist for cancer immunotherapy

Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner

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