{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lynn RC"],"funding":["Howard Hughes Medical Institute","NHGRI NIH HHS","NIH HHS"],"pagination":["293-300"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6944329"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["576(7786)"],"pubmed_abstract":["Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer<sup>1-3</sup>, but dysfunction due to T cell exhaustion is an important barrier to progress<sup>4-6</sup>. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion<sup>6</sup>. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells<sup>7-10</sup>. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents."],"journal":["Nature"],"pubmed_title":["c-Jun overexpression in CAR T cells induces exhaustion resistance."],"pmcid":["PMC6944329"],"funding_grant_id":["P50 HG007735","S10 OD018220","RM1 HG007735"],"pubmed_authors":["Majzner R","Xu P","Anbunathan H","Granja J","Chang HY","Weber EW","Good Z","Lynn RC","Nagaraja S","de Bourcy CFA","Sotillo E","Gennert D","Tieu V","Quake SR","Mackall CL","Satpathy AT","Jones R","Monje M","Lattin J"],"additional_accession":[]},"is_claimable":false,"name":"c-Jun overexpression in CAR T cells induces exhaustion resistance.","description":"Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer<sup>1-3</sup>, but dysfunction due to T cell exhaustion is an important barrier to progress<sup>4-6</sup>. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion<sup>6</sup>. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells<sup>7-10</sup>. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Dec","modification":"2024-11-15T22:55:19.206Z","creation":"2020-06-07T07:02:03Z"},"accession":"S-EPMC6944329","cross_references":{"pubmed":["31802004"],"doi":["10.1038/s41586-019-1805-z"]}}