Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles

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Abstract

Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS–STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them.

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Fig. 1: Nucleic acid sensing at the interface between cellular and organismal homeostasis.
Fig. 2: Revised pharmacological audit trail for modulators of NASs.
Fig. 3: Molecular crosstalk in mammalian nucleic acid sensing.

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Acknowledgements

The authors apologize to the authors of multiple preclinical and clinical studies on pharmacological modulators of the nucleic acid sensing machinery that could not be cited owing to space limitations. C.V.B. is supported by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA) and a Career Development Award from the Radiation Research Foundation (Kansas City, MI, USA). L.G. is supported by a Breakthrough Level 2 grant from the US Department of Defense, Breast Cancer Research Program (BC180476P1), by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, NY, USA) and by donations from Phosplatin (New York, NY, USA), the Luke Heller TECPR2 Foundation (Boston, MA, USA) and Sotio (Prague, Czech Republic).

Author information

C.V.B. and L.G. conceived this Review and wrote the first version of the manuscript, with constructive input from J.A.H. C.V.B. and L.G. prepared display items. All authors approved the final version of the manuscript.

Correspondence to Lorenzo Galluzzi.

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Competing interests

C.V.B. and J.H. have no relevant conflicts of interest. L.G. provides remunerated consulting to OmniSEQ (Buffalo, NY, USA), Astra Zeneca (Gaithersburg, MD, USA), VL47 (New York, NY, USA) and the Luke Heller TECPR2 Foundation (Boston, MA, USA), and is a member of the Scientific Advisory Committee of OmniSEQ (Buffalo, NY, USA).

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Glossary

Pattern recognition receptors

(PRRs). Members of an evolutionarily ancient group of receptors that initiate innate immunity on detection of conserved microbial products or endogenous damage-associated molecular patterns.

Damage-associated molecular patterns

Endogenous molecules with immunomodulatory activity that are exposed or secreted upon cellular damage or death, culminating in the activation of pattern recognition receptors on neighbouring cells.

CpG regions

Portions of a nucleic acid rich in unmethylated cytosine–guanine dimers.

Dendritic cell

(DC). Haematopoietic cell of myeloid derivation specialized in the uptake of antigens from the microenvironment and their presentation to T cells.

Cross-priming

Process whereby specific dendritic cell subsets initiate CD8+ (rather than CD4+) cell responses against antigens taken up from the microenvironment.

Immune checkpoint blocker

(ICB). Member of a class of drugs that mediate anticancer effects by inhibiting the molecular systems involved in the natural extinction of immune responses.

Plasmacytoid DCs

Particular variant of dendritic cells (DCs) that morphologically resemble plasma cells and secrete high levels of type I interferon in response to activatory signals.

Monocyte-derived DCs

Specific variant of dendritic cells (DCs) that originate from circulating monocytes on recruitment to sites of inflammation.

Viral interference

Process whereby virally infected cells establish resistance to infection locally via paracrine circuitries depending on type I interferon.

Imidazoquinolines

Organic molecules characterized by a tricyclic structure that has been frequently used as a lead for the development of TLR7 agonists.

CD4+ T helper cells

Lymphocytes that support and direct the activity of other immune cells, including CD8+ T cells, by releasing cytokines.

γδ T cells

Relatively rare variant of T cells that express a γδ (rather than the common αβ) T cell receptor, and hence are endowed with major histocompatibility complex-independent activity.

Monobenzone

Monobenzyl ether of hydroquinone, often used for medical depigmentation.

Nivolumab

Clinically used monoclonal antibody that acts by inhibiting programmed cell death 1 (PD-1), hence unleashing the effector function of T cells.

CD8+ cytotoxic T lymphocyte

(CTL). Lymphoid cell capable of mediating cytotoxic functions in response to a specific antigenic epitope presented on major histocompatibility complex class I molecules.

Natural killer cells

(NK cells). Lymphoid cells capable of mediating cytotoxic functions in an antigen-independent manner.

Cetuximab

Monoclonal antibody specific for epidermal growth factor receptor, commonly used in the clinic for the treatment of colorectal cancer and some forms of lung cancer.

Durvalumab

Clinically used monoclonal antibody that acts by inhibiting PD-L1, hence unleashing the effector function of T cells.

Oligodeoxynucleotides

Short nucleic acids based on a deoxyribose backbone.

Interferon-stimulated genes

(ISGs). Members of a large gene set that is upregulated in response to type I interferon signalling, such as MX1 or CXCL10.

Ribavirin

Commonly used antiviral medication that acts as a guanosine analogue, hence inhibiting viral replication and mRNA processing

TH1 cell cytokine

Cytokine that favours the polarization of the immune response towards a type 1 T helper cell (TH1 cell) profile, which is generally associated with robust antiviral and anticancer functions (for example, interferon-γ, tumour necrosis factor).

Regulated cell death

Variant of cell death that is mediated by a genetically encoded machinery, and hence can be modulated by pharmacological or genetic interventions.

Neoangiogenesis

Process whereby cancer cells initiate the vascularization of developing tumours, which is instrumental for disease progression and metastatic dissemination.

Myeloid-derived suppressor cells

Immature myeloid cells that mediate robust immunosuppressive effects, hence favouring cancer progression and resistance to therapy.

M2-like tumour-associated macrophages

Tumour-infiltrating macrophages that have immunosuppressive and proangiogenic function.

M1-like tumour-associated macrophages

Tumour-infiltrating macrophages that mediate immunostimulatory and inflammatory effects.

Pembrolizumab

Clinically used monoclonal antibody that acts by inhibiting programmed cell death 1 (PD-1), hence unleashing the effector function of T cells.

Abscopal response

In radiation oncology, the relatively rare phenomenon whereby irradiation of one malignant lesion results in objective responses at a non-irradiated disease site.

Inflammasome

Supramolecular platform that initiates the proteolytic maturation of proinflammatory cytokines such as IL-1β and IL-18.

Entecavir

Orally available antiviral medication that acts as a guanosine analogue, commonly used for the treatment of hepatitis B virus infection.

Tenofovir

Antiviral medication that acts as a reverse transcriptase inhibitor, commonly used for the treatment of hepatitis B virus infection and pre-exposure and post-exposure HIV-1 prophylaxis.

Small interfering RNAs

Short RNA duplexes extensively used for temporary gene silencing on transfection.

A-to-I editing

Post-transcriptional modification of RNA molecules that involves the enzymatic deamination of adenosine to inosine.

Non-oncogene addition

Concept identifying the dependency of some cancer cells on molecular functions that are not involved in oncogenesis.

Cyclic dinucleotides

(CDNs). Single-phosphate nucleotides with a cyclic bond arrangement between the sugar and phosphate groups, largely used by both prokaryotes and eukaryotes as a second messenger.

Systemic lupus erythematosus

(SLE). Systemic autoimmune disease in which the immune system mistakenly attacks healthy tissues, including the skin, joints, kidneys, brain and other organs.

Rheumatoid arthritis

Long-term autoimmune disorder that primarily affects joints, resulting in warmness, swelling and pain and ultimately leading to permanent joint destruction.

Synovial lining

The lining of the joints, normally only one or two cell layers thick, that is responsible for the production of the joint fluid.

Dermatomyositis

Acquired muscle disease that is characterized by chronic muscle inflammation accompanied by weakness.

Evans syndrome

Very rare autoimmune disorder in which the immune system destroys red blood cells, white blood cells and/or platelets.

Aicardi–Goutières syndrome

Inherited encephalopathy that affects newborns and is characterized by dysregulated type I interferon production.

Sjögren syndrome

Autoimmune disorder affecting salivary and tear glands that generally manifests itself with dry mouth and dry eyes.

Tumour-draining lymph nodes

Lymph nodes that collect extracellular fluids from the anatomical district where a malignant lesion is located.

Cytokine release syndrome

Potentially lethal side effect of some immunotherapies (including some nucleic acid sensor agonists) characterized by the widespread activation of immune cells and consequent release of large amounts of cytokines in the bloodstream.

Autophagy

Evolutionarily old homeostatic process culminating in the lysosomal degradation of superfluous, ectopic or potentially dangerous cytosolic entities.

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Vanpouille-Box, C., Hoffmann, J.A. & Galluzzi, L. Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles. Nat Rev Drug Discov 18, 845–867 (2019) doi:10.1038/s41573-019-0043-2

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