{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE267nnn/GSE267821/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE267821"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"4-1BB causes CAR-T cell death via sequestration of the ubiquitin-modifying enzyme A20","description":"CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell apoptosis and necroptosis in the absence of CAR tonic signaling. Additionally, we found that cell death induced by 4-1BB co-stimulation is TRAF and RIPK1-dependent. At the molecular level, 4-1BB endodomain causes functional deficiency of the A20 protein in CAR-T cells that appears to be sequestered at the plasma membrane through its binding to the 4-1BB in a TRAF-dependent manner. Genetic modulations of the A20 interplay with 4-1BB obtained by deletion of the TRAF binding motifs of 4-1BB rescue the cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.","dates":{"publication":"2026/05/18"},"accession":"GSE267821","cross_references":{"GSM":["GSM8279303","GSM8279302","GSM8279304","GSM8279284","GSM8279295","GSM8279294","GSM8279283","GSM8279297","GSM8279286","GSM8279296","GSM8279285","GSM8279299","GSM8279288","GSM8279287","GSM8279298","GSM8279301","GSM8279300","GSM8279289","GSM8279291","GSM8279290","GSM8279293","GSM8279292"],"GPL":["30173"],"GSE":["267821"],"taxon":["Homo sapiens"]}}