{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T07:02:21Z","timestamp":1779951741711,"version":"3.53.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n \n Chimeric antigen receptor T-cell (CAR-T) therapy is a potent treatment for relapsed\/refractory B-cell acute lymphoblastic leukemia (R\/R B-ALL). However, patients harboring\n TP53<\/jats:italic>\n alterations experience disproportionately high relapse rates, and the underlying tumor-intrinsic mechanisms driving this resistance remain poorly understood.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We engineered isogenic\n TP53<\/jats:italic>\n -wildtype and\n TP53<\/jats:italic>\n -knockout NALM-6 B-ALL cell models using CRISPR\/Cas9. The specific impact of p53 loss on CD19 CAR-T cell cytotoxicity, proliferation, and exhaustion was evaluated using\n in vitro<\/jats:italic>\n co-culture assays. Associated molecular alterations and adaptive responses were profiled via RNA-sequencing (RNA-seq).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In\n in vitro<\/jats:italic>\n assays,\n TP53<\/jats:italic>\n -deficient B-ALL cells exhibited intrinsic resistance to CAR-T-mediated killing. Co-culturing with these\n TP53<\/jats:italic>\n -null targets reduced CAR-T cell expansion, suppressed effector cytokine secretion, and accelerated a T-cell exhaustion phenotype, indicated by the co-expression of PD-1, TIM-3, and LAG-3. Transcriptomic profiling revealed that\n TP53<\/jats:italic>\n deficiency induces a low-adhesion signature, characterized by the coordinated downregulation of core extracellular matrix (ECM) and cell adhesion genes, including\n ITGB1<\/jats:italic>\n and\n LAMA5<\/jats:italic>\n . This transcriptional profile suggests a structural remodeling that potentially deprives CAR-T cells of the mechanical anchoring requisite for establishing a stable immunological synapse (IS). Furthermore,\n TP53<\/jats:italic>\n -deficient cells failed to activate immunogenic signaling pathways, such as IL-2\/STAT5, under immune pressure.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our\n in vitro<\/jats:italic>\n findings indicate that\n TP53<\/jats:italic>\n deficiency in B-ALL cells downregulates adhesion networks and impairs immunogenic signaling, which correlates with accelerated CAR-T cell exhaustion. These transcriptomic and cellular observations suggest a potential link between\n TP53<\/jats:italic>\n -mediated adhesion loss and CAR-T resistance, warranting further\n in vivo<\/jats:italic>\n validation and biophysical investigations.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1842309","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:15:28Z","timestamp":1779948928000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TP53 deficiency induces a low-adhesion transcriptomic signature correlating with accelerated CAR-T cell exhaustion in B-ALL"],"prefix":"10.3389","volume":"17","author":[{"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-juan","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-ping","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-dong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le-ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-pin","family":"Sui","sequence":"additional","affiliation":[{"name":"Molecular Diagnostic Center, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-min","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-025-02532-7","article-title":"Three-year analysis of adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in 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