Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells

dc.contributor.authorLee, DaeYongen
dc.contributor.authorHuntoon, Kristinen
dc.contributor.authorWang, Yifanen
dc.contributor.authorKang, Minjeongen
dc.contributor.authorLu, Yifeien
dc.contributor.authorJeong, Seong Dongen
dc.contributor.authorLink, Todd M.en
dc.contributor.authorGallup, Thomas D.en
dc.contributor.authorQie, Yaqingen
dc.contributor.authorLi, Xuefengen
dc.contributor.authorDong, Shiyanen
dc.contributor.authorSchrank, Benjamin R.en
dc.contributor.authorGrippin, Adam J.en
dc.contributor.authorAntony, Abinen
dc.contributor.authorHa, Jonghoonen
dc.contributor.authorChang, Mengyuen
dc.contributor.authorAn, Yien
dc.contributor.authorWang, Liangen
dc.contributor.authorJiang, Dadien
dc.contributor.authorLi, Jingen
dc.contributor.authorKoong, Albert C.en
dc.contributor.authorTainer, John A.en
dc.contributor.authorJiang, Wenen
dc.contributor.authorKim, Betty Y. S.en
dc.date.accessioned2025-02-19T13:03:43Zen
dc.date.available2025-02-19T13:03:43Zen
dc.date.issued2024-04-19en
dc.description.abstractIntracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses.en
dc.description.versionAccepted versionen
dc.format.extent32 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41551-024-01194-7en
dc.identifier.eissn2157-846Xen
dc.identifier.issn2157-846Xen
dc.identifier.issue5en
dc.identifier.orcidLee, DaeYong [0000-0001-8485-3577]en
dc.identifier.other10.1038/s41551-024-01194-7 (PII)en
dc.identifier.pmid38641710en
dc.identifier.urihttps://hdl.handle.net/10919/124647en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/38641710en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.meshAntigen-Presenting Cellsen
dc.subject.meshCell Line, Tumoren
dc.subject.meshAnimalsen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshBreast Neoplasmsen
dc.subject.meshCationsen
dc.subject.meshNucleotidyltransferasesen
dc.subject.meshPeptidesen
dc.subject.meshMembrane Proteinsen
dc.subject.meshFemaleen
dc.subject.meshToll-Like Receptor 9en
dc.subject.meshImmunity, Innateen
dc.titleSynthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cellsen
dc.title.serialNature Biomedical Engineeringen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2024-03-01en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/University Research Institutesen
pubs.organisational-groupVirginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

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