Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence
dc.contributor.author | Le, Phuong T. | en |
dc.contributor.author | Ha, Ngoc | en |
dc.contributor.author | Tran, Ngan K. | en |
dc.contributor.author | Newman, Andrew G. | en |
dc.contributor.author | Esselen, Katharine M. | en |
dc.contributor.author | Dalrymple, John L. | en |
dc.contributor.author | Schmelz, Eva M. | en |
dc.contributor.author | Bhandoola, Avinash | en |
dc.contributor.author | Xue, Hai-Hui | en |
dc.contributor.author | Singh, Prim | en |
dc.contributor.author | Thai, To-Ha | en |
dc.date.accessioned | 2022-03-23T16:46:29Z | en |
dc.date.available | 2022-03-23T16:46:29Z | en |
dc.date.issued | 2021-10-06 | en |
dc.description.abstract | Immune 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.notes | Funding This work was supported by NIH grants AI099012, CA198263, Friends for Life Neuroblastoma Research Program and The Mayer Family Fund. | en |
dc.description.sponsorship | NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI099012, CA198263] | en |
dc.description.version | Published version | en |
dc.format.mimetype | application/pdf | en |
dc.identifier.doi | https://doi.org/10.3389/fimmu.2021.738958 | en |
dc.identifier.issn | 1664-3224 | en |
dc.identifier.other | 738958 | en |
dc.identifier.pmid | 34721405 | en |
dc.identifier.uri | http://hdl.handle.net/10919/109430 | en |
dc.identifier.volume | 12 | en |
dc.language.iso | en | en |
dc.rights | Creative Commons Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
dc.subject | Cbx3/HP1 gamma | en |
dc.subject | LEF-1 | en |
dc.subject | IL-21 receptor | en |
dc.subject | CD8+T-cell persistence | en |
dc.subject | ovarian cancer | en |
dc.subject | melanoma | en |
dc.title | Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence | en |
dc.title.serial | Frontiers in Immunology | en |
dc.type | Article - Refereed | en |
dc.type.dcmitype | Text | en |
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