DC Field | Value | Language |
---|---|---|
dc.contributor.author | Kim, Segi | ko |
dc.contributor.author | Park, Cho I. | ko |
dc.contributor.author | Lee, Sunhwa | ko |
dc.contributor.author | Choi, Hyeong Ryeol | ko |
dc.contributor.author | Kim, Chan Hyuk | ko |
dc.date.accessioned | 2023-02-28T02:02:03Z | - |
dc.date.available | 2023-02-28T02:02:03Z | - |
dc.date.created | 2023-02-28 | - |
dc.date.created | 2023-02-28 | - |
dc.date.issued | 2023-01 | - |
dc.identifier.citation | FRONTIERS IN IMMUNOLOGY, v.14 | - |
dc.identifier.issn | 1664-3224 | - |
dc.identifier.uri | http://hdl.handle.net/10203/305388 | - |
dc.description.abstract | IntroductionAlthough the engineering of T cells to co-express immunostimulatory cytokines has been shown to enhance the therapeutic efficacy of adoptive T cell therapy, the uncontrolled systemic release of potent cytokines can lead to severe adverse effects. To address this, we site-specifically inserted the interleukin-12 (IL-12) gene into the PDCD1 locus in T cells using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based genome editing to achieve T-cell activation-dependent expression of IL-12 while ablating the expression of inhibitory PD-1. MethodsNew York esophageal squamous cell carcinoma 1(NY-ESO-1)-specific TCR-T cells was investigated as a model system. We generated Delta PD-1-IL-12 -edited NY-ESO-1 TCR-T cells by sequential lentiviral transduction and CRISPR knock-in into activated human primary T cells. ResultsWe showed that the endogenous PDCD1 regulatory elements can tightly control the secretion of recombinant IL-12 in a target cell-dependent manner, at an expression level that is more moderate than that obtained using a synthetic NFAT-responsive promoter. The inducible expression of IL-12 from the PDCD1 locus was sufficient to enhance the effector function of NY-ESO-1 TCR-T cells, as determined by upregulation of effector molecules, increased cytotoxic activity, and enhanced expansion upon repeated antigen stimulation in vitro. Mouse xenograft studies also revealed that PD-1-edited IL-12-secreting NY-ESO-1 TCR-T cells could eliminate established tumors and showed significantly greater in vivo expansion capacity than control TCR-T cells. DiscussionOur approach may provide a way to safely harness the therapeutic potential of potent immunostimulatory cytokines for the development of effective adoptive T cell therapies against solid tumors. | - |
dc.language | English | - |
dc.publisher | FRONTIERS MEDIA SA | - |
dc.title | Reprogramming of IL-12 secretion in the PDCD1 locus improves the anti-tumor activity of NY-ESO-1 TCR-T cells | - |
dc.type | Article | - |
dc.identifier.wosid | 000931118100001 | - |
dc.identifier.scopusid | 2-s2.0-85147828891 | - |
dc.type.rims | ART | - |
dc.citation.volume | 14 | - |
dc.citation.publicationname | FRONTIERS IN IMMUNOLOGY | - |
dc.identifier.doi | 10.3389/fimmu.2023.1062365 | - |
dc.contributor.localauthor | Kim, Chan Hyuk | - |
dc.contributor.nonIdAuthor | Lee, Sunhwa | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordAuthor | immunotherapy | - |
dc.subject.keywordAuthor | TCR-T | - |
dc.subject.keywordAuthor | interleukin-12 | - |
dc.subject.keywordAuthor | CRISPR | - |
dc.subject.keywordAuthor | Cas9 | - |
dc.subject.keywordAuthor | NY-ESO-1 | - |
dc.subject.keywordAuthor | PD-1 | - |
dc.subject.keywordPlus | TUMOR-INFILTRATING LYMPHOCYTES | - |
dc.subject.keywordPlus | INTERFERON-GAMMA | - |
dc.subject.keywordPlus | IN-VITRO | - |
dc.subject.keywordPlus | PD-1 | - |
dc.subject.keywordPlus | INTERLEUKIN-12 | - |
dc.subject.keywordPlus | EXPRESSION | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | CAR | - |
dc.subject.keywordPlus | PERSISTENCE | - |
dc.subject.keywordPlus | PROMOTES | - |
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