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Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations

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dc.contributor.authorPang, E.S.
dc.contributor.authorDaraj, G.
dc.contributor.authorBalka, K.R.
dc.contributor.authorDe Nardo, D.
dc.contributor.authorMacri, C.
dc.contributor.authorHochrein, H.
dc.contributor.authorMasterman, K.A.
dc.contributor.authorTan, P.S.
dc.contributor.authorShoppee, A.
dc.contributor.authorMagill, Z.
dc.contributor.authorJahan, N.
dc.contributor.authorBafit, M.
dc.contributor.authorZhan, Y.
dc.contributor.authorKile, B.T.
dc.contributor.authorLawlor, K.E.
dc.contributor.authorRadford, K.J.
dc.contributor.authorWright, M.D.
dc.contributor.authorO'Keeffe, M.
dc.date.issued2022
dc.description.abstractStimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-ls) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-l1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.
dc.description.statementofresponsibilityEe Shan Pang, Ghazal Daraj, Katherine R. Balka, Dominic De Nardo, Christophe Macri, Hubertus Hochrein, Kelly-Anne Masterman, Peck S. Tan, Angus Shoppee, Zoe Magill, Nazneen Jahan, Mariam Bafit, Yifan Zhan, Benjamin T. Kile, Kate E. Lawlor, Kristen J. Radford, Mark D. Wright, and Meredith O, Keeffe
dc.identifier.citationFrontiers in Immunology, 2022; 13:794776-1-794776-19
dc.identifier.doi10.3389/fimmu.2022.794776
dc.identifier.issn1664-3224
dc.identifier.issn1664-3224
dc.identifier.orcidKile, B.T. [0000-0002-8836-8947]
dc.identifier.urihttps://hdl.handle.net/2440/135026
dc.language.isoen
dc.publisherFrontiers Media SA
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1077633
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1085934
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1145788
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1162765
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/11801089
dc.relation.granthttp://purl.org/au-research/grants/arc/FT190100266
dc.rightsCopyright © 2022 Pang, Daraj, Balka, De Nardo, Macri, Hochrein, Masterman, Tan, Shoppee, Magill, Jahan, Bafit, Zhan, Kile, Lawlor, Radford, Wright and O’Keeffe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.source.urihttps://doi.org/10.3389/fimmu.2022.794776
dc.subjectSTING activation
dc.subjectdendritic cell (DC)
dc.subjectinterferon-lambda
dc.subjecthuman dendritic cells
dc.subjecttype III interferons
dc.subjectcell death
dc.subjectplasmacytoid dendritic cells (pDCs)
dc.titleDiscordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations
dc.typeJournal article
pubs.publication-statusPublished

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