Reprogramming of IL-12 secretion in the PDCD1 locus improves the anti-tumor activity of NY-ESO-1 TCR-T cells

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dc.contributor.authorKim, Segiko
dc.contributor.authorPark, Cho I.ko
dc.contributor.authorLee, Sunhwako
dc.contributor.authorChoi, Hyeong Ryeolko
dc.contributor.authorKim, Chan Hyukko
dc.date.accessioned2023-02-28T02:02:03Z-
dc.date.available2023-02-28T02:02:03Z-
dc.date.created2023-02-28-
dc.date.created2023-02-28-
dc.date.issued2023-01-
dc.identifier.citationFRONTIERS IN IMMUNOLOGY, v.14-
dc.identifier.issn1664-3224-
dc.identifier.urihttp://hdl.handle.net/10203/305388-
dc.description.abstractIntroductionAlthough 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.languageEnglish-
dc.publisherFRONTIERS MEDIA SA-
dc.titleReprogramming of IL-12 secretion in the PDCD1 locus improves the anti-tumor activity of NY-ESO-1 TCR-T cells-
dc.typeArticle-
dc.identifier.wosid000931118100001-
dc.identifier.scopusid2-s2.0-85147828891-
dc.type.rimsART-
dc.citation.volume14-
dc.citation.publicationnameFRONTIERS IN IMMUNOLOGY-
dc.identifier.doi10.3389/fimmu.2023.1062365-
dc.contributor.localauthorKim, Chan Hyuk-
dc.contributor.nonIdAuthorLee, Sunhwa-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorimmunotherapy-
dc.subject.keywordAuthorTCR-T-
dc.subject.keywordAuthorinterleukin-12-
dc.subject.keywordAuthorCRISPR-
dc.subject.keywordAuthorCas9-
dc.subject.keywordAuthorNY-ESO-1-
dc.subject.keywordAuthorPD-1-
dc.subject.keywordPlusTUMOR-INFILTRATING LYMPHOCYTES-
dc.subject.keywordPlusINTERFERON-GAMMA-
dc.subject.keywordPlusIN-VITRO-
dc.subject.keywordPlusPD-1-
dc.subject.keywordPlusINTERLEUKIN-12-
dc.subject.keywordPlusEXPRESSION-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusCAR-
dc.subject.keywordPlusPERSISTENCE-
dc.subject.keywordPlusPROMOTES-
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