Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity

McAndrews, Kathleen M.; P.Y., Sara; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1016/j.jbc.2021.100523

Cited by 50 publications

(39 citation statements)

References 39 publications

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“…Importantly, evACE2 possesses an 80-fold better efficiency to block SARS-CoV-2 infection than soluble rhACE2. Of note, it has been recently reported that the exosomal delivery of STINGa potentiates its uptake into dendritic cells compared with STINGa alone, which led to increased accumulation of activated CD8 + T-cells and an antitumor immune response 61 .…”

Section: Discussionmentioning

confidence: 99%

Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2

et al. 2022

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with evolving variants of concern. It remains urgent to identify novel approaches against broad strains of SARS-CoV-2, which infect host cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). Herein, we report an increase in circulating extracellular vesicles (EVs) that express ACE2 (evACE2) in plasma of COVID-19 patients, which levels are associated with severe pathogenesis. Importantly, evACE2 isolated from human plasma or cells neutralizes SARS-CoV-2 infection by competing with cellular ACE2. Compared to vesicle-free recombinant human ACE2 (rhACE2), evACE2 shows a 135-fold higher potency in blocking the binding of the viral spike protein RBD, and a 60- to 80-fold higher efficacy in preventing infections by both pseudotyped and authentic SARS-CoV-2. Consistently, evACE2 protects the hACE2 transgenic mice from SARS-CoV-2-induced lung injury and mortality. Furthermore, evACE2 inhibits the infection of SARS-CoV-2 variants (α, β, and δ) with equal or higher potency than for the wildtype strain, supporting a broad-spectrum antiviral mechanism of evACE2 for therapeutic development to block the infection of existing and future coronaviruses that use the ACE2 receptor.

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Section: Discussionmentioning

confidence: 99%

Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2

et al. 2022

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“…Synthetic nanoparticles assembled in the presence of CDNs have been shown to enhance cytosolic delivery and activate STING-dependent anti-tumor responses (Lu et al, 2020;Wilson et al, 2018). Exosomes loaded with CDNs appear to achieve similar enhancements (Jang et al, 2021;McAndrews et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Cellular selectivity of STING stimulation determines priming of tumor-specific T cell responses

Jneid

Bochnakian

Delisle

et al. 2021

Preprint

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T cells that recognize tumor antigens are crucial for anti-tumor immune responses. Induction of anti-tumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDNs). However, the optimal way to leverage STING activation in non-immunogenic tumors is still unclear. Here, we show that cGAMP delivery by intra-tumoral injection of virus-like particles (cGAMP-VLP) leads to differentiation of tumor-specific T cells, decrease in tumor regulatory T cells (Tregs) and anti-tumoral responses that synergize with PD1 blockade. By contrast, intra-tumoral injection of synthetic CDN leads to tumor necrosis and systemic T cell activation but no differentiation of tumor-specific T cells, and a demise of immune cells in injected tumors. Analyses of cytokine responses and genetic models revealed that cGAMP-VLP preferentially targets STING in dendritic cells at a 1000-fold less dose than synthetic CDN. Sub-cutaneous administration of cGAMP-VLP showed synergy when combined with a tumor Treg-depleting antibody to elicit systemic tumor-specific T cells, leading to complete and lasting tumor eradication. These finding show that cell targeting of STING stimulation shapes the anti-tumor T cell response and reveal a therapeutic strategy with T cell modulators.

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“…McAndrews et al used exosomes loaded with STING’s GMP-AMP cyclic agonist (iExoSTINGa) to specifically target the STING pathway in APCs with greater efficacy than STINGa alone in inhibiting B16F10 cancer proliferation. Furthermore, iExoSTINGa showed greater uptake of STINGa in dendritic cells than STINGa alone, with a significant increase in stimulated CD8 + T cells and an improved antitumor immune response [ 113 ].…”

Section: Exosomes and Breast Cancermentioning

confidence: 99%

Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies

Allegra

Petrarca

Gioacchino

et al. 2022

Cells

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Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit tumor onset and diffusion in diverse solid and hematological malignancies by paracrine signaling. Thus, exosomes might constitute a promising cell-free tumor treatment alternative. This review focuses on the effects of exosomes in the treatment of tumors, by discussing the most recent and promising data from in vitro and experimental in vivo studies and the few existing clinical trials. Exosomes are extremely promising as transporters of drugs, antagomir, genes, and other therapeutic substances that can be integrated into their core via different procedures. Moreover, exosomes can augment or inhibit non-coding RNAs, change the metabolism of cancer cells, and modify the function of immunologic effectors thus modifying the tumor microenvironment transforming it from pro-tumor to antitumor milieu. Here, we report the development of currently realized exosome modifiers that offer indications for the forthcoming elaboration of other more effective methods capable of enhancing the activity of the exosomes.

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Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity

Cited by 50 publications

References 39 publications

Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2

Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2

Cellular selectivity of STING stimulation determines priming of tumor-specific T cell responses

Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies

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