{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:03:33Z","timestamp":1789016613441,"version":"build-2803163510"},"reference-count":32,"publisher":"American Society of Hematology","issue":"21","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,5,23]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of \u223c85% in children and &amp;lt;50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T-cell receptor (TCR) in T-ALL with anti-CD3 (\u03b1CD3) monoclonal antibodies (mAbs) enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development; induces leukemic cell death; and impairs leukemia progression to ultimately improve host survival. However, \u03b1CD3 monotherapy resulted in relapse. To find out actionable targets able to re-enforce leukemic cells\u2019 vulnerability to \u03b1CD3 mAbs, including the clinically relevant teplizumab, we identified the molecular program induced by \u03b1CD3 mAbs in patient-derived xenografts derived from T-ALL cases. Using large-scale transcriptomic analysis, we found prominent expression of tumor necrosis factor \u03b1 (TNF\u03b1), lymphotoxin \u03b1 (LT\u03b1), and multiple components of the \u201cTNF\u03b1 via NF-\u03baB signaling\u201d pathway in anti-CD3\u2013treated T-ALL. We show in\u00a0vivo that etanercept, a sink for TNF\u03b1\/LT\u03b1, enhances \u03b1CD3 antileukemic properties, indicating that TNF\/TNF receptor (TNFR) survival pathways interferes with TCR-induced leukemic cell death. However, suppression of TNF-mediated survival and switch to TNFR-mediated cell death through inhibition of cellular inhibitor of apoptosis protein-1\/2 (cIAP1\/2) with the second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant synergizes with \u03b1CD3 to impair leukemia expansion in a receptor-interacting serine\/threonine-protein kinase 1\u2013dependent manner and improve mice survival. Thus, our results advocate the use of either TNF\u03b1\/LT\u03b1 inhibitors, or birinapant\/other SMAC mimetics to improve anti-CD3 immunotherapy in T-ALL.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022455","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T22:29:30Z","timestamp":1709591370000},"page":"2166-2177","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":14,"title":["Targeting the TNF\/IAP pathway synergizes with anti-CD3 immunotherapy in T-cell acute lymphoblastic leukemia"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1203-0616","authenticated-orcid":false,"given":"Andrea","family":"\u00c1vila \u00c1vila","sequence":"first","affiliation":[{"name":"1Institut Curie, Orsay, France"},{"name":"2Centre National de la Recherche Scientifique UMR3348, Centre Universitaire, Orsay, France"},{"name":"3INSERM, U1278, Orsay, 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