Targeting the TNF/IAP pathway synergizes with anti-CD3 immunotherapy in T-cell acute lymphoblastic leukemia.
Blood
; 143(21): 2166-2177, 2024 May 23.
Article
em En
| MEDLINE
| ID: mdl-38437728
ABSTRACT
ABSTRACT T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of â¼85% in children and <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 (αCD3) 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, αCD3 monotherapy resulted in relapse. To find out actionable targets able to re-enforce leukemic cells' vulnerability to αCD3 mAbs, including the clinically relevant teplizumab, we identified the molecular program induced by αCD3 mAbs in patient-derived xenografts derived from T-ALL cases. Using large-scale transcriptomic analysis, we found prominent expression of tumor necrosis factor α (TNFα), lymphotoxin α (LTα), and multiple components of the "TNFα via NF-κB signaling" pathway in anti-CD3-treated T-ALL. We show in vivo that etanercept, a sink for TNFα/LTα, enhances αCD3 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 αCD3 to impair leukemia expansion in a receptor-interacting serine/threonine-protein kinase 1-dependent manner and improve mice survival. Thus, our results advocate the use of either TNFα/LTα inhibitors, or birinapant/other SMAC mimetics to improve anti-CD3 immunotherapy in T-ALL.
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Base de dados:
MEDLINE
Assunto principal:
Fator de Necrose Tumoral alfa
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Complexo CD3
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article