Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

dc.contributor.authorLe, Phuong T.en
dc.contributor.authorHa, Ngocen
dc.contributor.authorTran, Ngan K.en
dc.contributor.authorNewman, Andrew G.en
dc.contributor.authorEsselen, Katharine M.en
dc.contributor.authorDalrymple, John L.en
dc.contributor.authorSchmelz, Eva M.en
dc.contributor.authorBhandoola, Avinashen
dc.contributor.authorXue, Hai-Huien
dc.contributor.authorSingh, Primen
dc.contributor.authorThai, To-Haen
dc.date.accessioned2022-03-23T16:46:29Zen
dc.date.available2022-03-23T16:46:29Zen
dc.date.issued2021-10-06en
dc.description.abstractImmune checkpoint blockade (ICB) relieves CD8(+) T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8(+) T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting Cbx3/HP1 gamma in CD8(+) T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at Lef1 and Il21r. LEF-1 and IL-21R are necessary for Cbx3/HP1 gamma-deficient CD8(+) effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of Cbx3/HP1 gamma-deficient CD8(+) T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4(+) Tregs. Thus, CD8(+) T cells heightened effector function consequent to Cbx3/HP1 gamma deficiency may be distinct from functional reactivation by ICB, implicating Cbx3/HP1 gamma as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.</p>en
dc.description.notesFunding This work was supported by NIH grants AI099012, CA198263, Friends for Life Neuroblastoma Research Program and The Mayer Family Fund.en
dc.description.sponsorshipNIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI099012, CA198263]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fimmu.2021.738958en
dc.identifier.issn1664-3224en
dc.identifier.other738958en
dc.identifier.pmid34721405en
dc.identifier.urihttp://hdl.handle.net/10919/109430en
dc.identifier.volume12en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCbx3/HP1 gammaen
dc.subjectLEF-1en
dc.subjectIL-21 receptoren
dc.subjectCD8+T-cell persistenceen
dc.subjectovarian canceren
dc.subjectmelanomaen
dc.titleTargeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistenceen
dc.title.serialFrontiers in Immunologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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