Anti-thymocyte globulin triggers TNF-dependent cell death in T-cell acute lymphoblastic leukemia
T-cell acute lymphoblastic leukemia (T-ALL) accounts for one of the most aggressive hematological tumors associated with poor prognosis, notably for relapsed and refractory patients. Hence, an unmet medical need persists for T-ALL patients who fail to durably respond to conventional treatments. Herein, we report the antileukemic efficacy of anti-thymocyte globulin (ATG), a polyclonal cocktail of IgG enriched in antibodies directed against human thymocyte antigens. The treatment of preclinical models of T-ALL reveals a cytotoxic mechanism of ATG mediated by TNFα signaling. We demonstrate that ATG resistance may occur via the induction of negative regulators of TNFα-induced cell death and can be circumvented by SMAC mimetic birinapant ex vivo and in vivo. These results are validated in a series of prospective primary relapsed/refractory T-ALL samples. Here, we provide a strong rationale for clinically relevant ATG-based immunotherapy in combination with birinapant to treat T-ALL patients. Anti-thymocyte globulin (ATG) is a potent immunosuppressant used to prevent and treat acute organ transplant rejection and severe aplastic anemia. Here, the authors discover that ATG can be repurposed to induce TNF-driven cell death in T cell acute lymphoblastic leukemia.
Authors
- Hervé Dombret (ORCID: https://orcid.org/0000-0002-5454-6768)
- Étienne Lengliné (ORCID: https://orcid.org/0000-0003-0965-6615)
- Christine Tran Quang (ORCID: https://orcid.org/0000-0002-1003-2626)
- Aurore Touzart (ORCID: https://orcid.org/0000-0002-8888-2292)
- Lucien Courtois (ORCID: https://orcid.org/0000-0002-4156-3008)
- Marie-Émilie Dourthe (ORCID: https://orcid.org/0000-0002-8326-5973)
- Mehdi Latiri (ORCID: https://orcid.org/0009-0005-1520-4633)
- Norbert Ifrah (ORCID: https://orcid.org/0000-0003-3063-850X)
- Mathieu Simonin (ORCID: https://orcid.org/0000-0002-0448-8811)
- Vahid Asnafi (ORCID: https://orcid.org/0000-0002-6255-5314)
- Guillaume P. Andrieu (ORCID: https://orcid.org/0000-0003-0289-4952)
- Olivier Hermine (ORCID: https://orcid.org/0000-0003-2574-3874)
- Elizabeth Macintyre (ORCID: https://orcid.org/0000-0003-0520-0493)
- Agata Cieślak (ORCID: https://orcid.org/0000-0003-1015-9448)
- Chaimae Saji
- Nicolas Boissel (ORCID: https://orcid.org/0000-0003-2091-7927)
- Guillaume Charbonnier (ORCID: https://orcid.org/0000-0001-5615-1287)
- Jacques Ghysdael
- Jérome Doss
- Grégoire Huré
- Camille Gillet (ORCID: https://orcid.org/0000-0002-6976-0636)
- André Baruchel
- Philippe Rousselot
Institutions
- University of London Institute in Paris (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Nantes Angers Le Mans (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Hôpital Armand-Trousseau (FR)
- Institut des Sciences des Plantes de Paris Saclay (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre Hospitalier Universitaire d'Angers (FR)
- CEA Paris-Saclay (FR)
- Hôpital Saint-Louis (FR)
- Centre Hospitalier de Versailles (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Institut de recherche Saint-Louis (FR)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-19
- DOI
- https://doi.org/10.1038/s41467-026-77027-9
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.00