Anti-thymocyte globulin triggers TNF-dependent cell death in T-cell acute lymphoblastic leukemia
Abstract
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.
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Authors: Marie-Émilie Dourthe, Mehdi Latiri, Étienne Lengliné, Guillaume Charbonnier, Chaimae Saji, Grégoire Huré, Camille Gillet, Jérome Doss, Aurore Touzart, Lucien Courtois, Agata Cieślak, Mathieu Simonin, Norbert Ifrah, Hervé Dombret, Olivier Hermine, Nicolas Boissel, André Baruchel, Jacques Ghysdael, Elizabeth Macintyre, Philippe Rousselot, Christine Tran Quang, Guillaume P. Andrieu, Vahid Asnafi
Institutions: Inserm, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris Cité, Sorbonne Université, Centre National de la Recherche Scientifique, Assistance Publique – Hôpitaux de Paris, CEA Paris-Saclay, Institut Curie, Centre Hospitalier Universitaire d'Angers, Centre Hospitalier de Versailles, Hôpital Saint-Louis, Hôpital Necker-Enfants Malades, Institut des Sciences des Plantes de Paris Saclay, Institut Necker Enfants Malades, Institut des Maladies Génétiques Imagine, Hôpital Armand-Trousseau, Université Nantes Angers Le Mans, University of London Institute in Paris, Institut de recherche Saint-Louis