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TNF-mediated cell death: an actionable target for immunotherapy in T-ALL [1]

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) accounts for one of the most aggressive hematological tumors and remains associated with poor prognosis and dismal outcomes, notably for relapsed and refractory patients. Unlike leukemias of myeloid or B-cell origin, T-ALL has not benefited from the major advances in immune and cell-based therapies. Hence, an unmet medical need persists for underserved T-ALL patients who fail to durably respond to conventional treatments. Herein, we report the robust antileukemic efficacy of ATG, a polyclonal cocktail of IgG enriched in human thymocyte antigens, in vivo. The treatment of a large series of preclinical models of T-ALL revealed a genuine cytotoxic mechanism of ATG mediated by TNF signaling. Critically, we revealed that ATG resistance may occur via the induction of negative regulators of TNF-induced cell death, and can be circumvented by SMAC mimetic birinapant ex vivo and in vivo. These promising results were validated in an important series of prospective primary R/R T-ALL samples. This study provides a strong rationale for clinically relevant ATG-based immunotherapy in combination with birinapant to better treat T-ALL patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266344 | GEO | 2026/05/31

REPOSITORIES: GEO

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Project description:Metastatic malignant melanoma is the deadliest skin cancer type, and it is characterized by its high resistance to apoptosis. The main driving mutations in melanoma cause hyperactivation of genes within the ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in this cancer type. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the pro-apoptotic MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the pro-apoptotic MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the anti-apoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of the apoptotic regulator that bind to SMAC and LATS1. Mechanistic analysis show that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the pro-apoptotic signal mediated by the LAST1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant which requires the inhibition of C-IAP1 and the degradation of XIAP, indicating that the MST2/Hippo pathway is part of the mechanism of action of Birinapant. Overall, the current work shows SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the RAF/ERK pathway.

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TNF-mediated cell death: an actionable target for immunotherapy in T-ALL [1]

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