Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses

Jiang, Xiaodong; Muthusamy, Viswanathan; Fedorova, Olga; Kong, Yong; Kim, Daniel J.; Bosenberg, Marcus W.; Pyle, Anna Marie; Iwasaki, Akiko

doi:10.1084/jem.20190801

Cited by 54 publications

(87 citation statements)

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“…Recent work established the validity of activating PRRs as a strategy to enhance a therapeutic immune response against tumors. Agonists of STING and RIG-I have shown promise in mouse models as standalone or adjuvants for enhancing immunotherapies (Elion et al 2018;Ramanjulu et al 2018;Heidegger et al 2019;Jiang et al 2019). Conversely, in some contexts, interferon signaling is beneficial to tumor growth (Khodarev et al 2012;Boelens et al 2014;Nabet et al 2017).…”

Section: Discussionmentioning

confidence: 99%

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

et al. 2020

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Deciphering the mechanisms that regulate the sensitivity of pathogen recognition receptors is imperative to understanding infection and inflammation. Here we demonstrate that the RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) acts on both host and virus-derived 5′-triphosphate RNAs rendering them less active in inducing a RIG-I-mediated immune response. Reducing DUSP11 levels alters host triphosphate RNA packaged in extracellular vesicles and induces enhanced RIG-I activation in cells exposed to extracellular vesicles. Virus infection of cells lacking DUSP11 results in a higher proportion of triphosphorylated viral transcripts and attenuated virus replication, which is rescued by reducing RIG-I expression. Consistent with the activity of DUSP11 in the cellular RIG-I response, mice lacking DUSP11 display lower viral loads, greater sensitivity to triphosphorylated RNA, and a signature of enhanced interferon activity in select tissues. Our results reveal the importance of controlling 5′-triphosphate RNA levels to prevent aberrant RIG-I signaling and demonstrate DUSP11 as a key effector of this mechanism.

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Section: Discussionmentioning

confidence: 99%

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

et al. 2020

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“…these showed promising results in several cancer models [183][184][185] , as well as in augmenting immunity [186][187][188] . additionally, activation of riG-i signalling by 5′-PPP rNa was shown to facilitate tumour responsiveness to checkpoint inhibitors 189,190 . Furthermore, in vitro synthesized circular RNAs have been proposed to activate RIG-I, and such RNA preparations induce antitumour responses in an in vivo model 191,192 .…”

Section: Box 2 | Therapeutic Approaches and Synthetic Rlr Agonistsmentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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| Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review , we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally , we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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“…Live attenuated microbes are often more effective in long-term protection against infectious diseases than subunit vaccines. Therefore, it can be postulated that live attenuated NDV as adjuvant in a cancer vaccine is superior to subunits, such as agonists to RIG-I [97] or Toll-like receptor (TLR). The molecular details of stimulating innate immunity via live attenuated NDV include (i) the activation of NK cells via HN interacting with NKp46 [98], (ii) activation of monocytes, macrophages, and DCs via NFκB, thus inducing a module for pro-inflammatory cytokines (TNFα, IL-2, IL-15, IFNα, IFN-γ) [99,100], (iii) re-programming DCs within 18 hrs of infection into polarization towards DC1 [101], (iv) upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [102], and v) the induction of nitric oxide (NO) [99].…”

Section: Discussionmentioning

confidence: 99%

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

Schirrmacher¹

2020

Biomedicines

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The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.

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Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses

Abstract: The authors examined a specific RIG-I agonist, SLR14, as an antitumor agent in mice. Intratumoral administration of SLR14 induces robust and long-term antitumor responses against primary, distal, and metastatic tumor as a single agent and improves efficacy of anti-PD1 therapy.

Cited by 54 publications

References 54 publications

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

RIG-I-like receptors: their regulation and roles in RNA sensing

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

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