Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells
dc.contributor.author | Lee, DaeYong | en |
dc.contributor.author | Huntoon, Kristin | en |
dc.contributor.author | Wang, Yifan | en |
dc.contributor.author | Kang, Minjeong | en |
dc.contributor.author | Lu, Yifei | en |
dc.contributor.author | Jeong, Seong Dong | en |
dc.contributor.author | Link, Todd M. | en |
dc.contributor.author | Gallup, Thomas D. | en |
dc.contributor.author | Qie, Yaqing | en |
dc.contributor.author | Li, Xuefeng | en |
dc.contributor.author | Dong, Shiyan | en |
dc.contributor.author | Schrank, Benjamin R. | en |
dc.contributor.author | Grippin, Adam J. | en |
dc.contributor.author | Antony, Abin | en |
dc.contributor.author | Ha, Jonghoon | en |
dc.contributor.author | Chang, Mengyu | en |
dc.contributor.author | An, Yi | en |
dc.contributor.author | Wang, Liang | en |
dc.contributor.author | Jiang, Dadi | en |
dc.contributor.author | Li, Jing | en |
dc.contributor.author | Koong, Albert C. | en |
dc.contributor.author | Tainer, John A. | en |
dc.contributor.author | Jiang, Wen | en |
dc.contributor.author | Kim, Betty Y. S. | en |
dc.date.accessioned | 2025-02-19T13:03:43Z | en |
dc.date.available | 2025-02-19T13:03:43Z | en |
dc.date.issued | 2024-04-19 | en |
dc.description.abstract | Intracellular 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.version | Accepted version | en |
dc.format.extent | 32 page(s) | en |
dc.format.mimetype | application/pdf | en |
dc.identifier.doi | https://doi.org/10.1038/s41551-024-01194-7 | en |
dc.identifier.eissn | 2157-846X | en |
dc.identifier.issn | 2157-846X | en |
dc.identifier.issue | 5 | en |
dc.identifier.orcid | Lee, DaeYong [0000-0001-8485-3577] | en |
dc.identifier.other | 10.1038/s41551-024-01194-7 (PII) | en |
dc.identifier.pmid | 38641710 | en |
dc.identifier.uri | https://hdl.handle.net/10919/124647 | en |
dc.identifier.volume | 8 | en |
dc.language.iso | en | en |
dc.publisher | Nature Portfolio | en |
dc.relation.uri | https://www.ncbi.nlm.nih.gov/pubmed/38641710 | en |
dc.rights | In Copyright | en |
dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
dc.subject.mesh | Antigen-Presenting Cells | en |
dc.subject.mesh | Cell Line, Tumor | en |
dc.subject.mesh | Animals | en |
dc.subject.mesh | Mice, Inbred C57BL | en |
dc.subject.mesh | Humans | en |
dc.subject.mesh | Mice | en |
dc.subject.mesh | Breast Neoplasms | en |
dc.subject.mesh | Cations | en |
dc.subject.mesh | Nucleotidyltransferases | en |
dc.subject.mesh | Peptides | en |
dc.subject.mesh | Membrane Proteins | en |
dc.subject.mesh | Female | en |
dc.subject.mesh | Toll-Like Receptor 9 | en |
dc.subject.mesh | Immunity, Innate | en |
dc.title | Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells | en |
dc.title.serial | Nature Biomedical Engineering | en |
dc.type | Article - Refereed | en |
dc.type.dcmitype | Text | en |
dc.type.other | Article | en |
dc.type.other | Journal | en |
dcterms.dateAccepted | 2024-03-01 | en |
pubs.organisational-group | Virginia Tech | en |
pubs.organisational-group | Virginia Tech/All T&R Faculty | en |
pubs.organisational-group | Virginia Tech/University Research Institutes | en |
pubs.organisational-group | Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTC | en |