Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia
Menée à l'aide de modèles murins de leucémie lymphoblastique aiguë T, cette étude française met en évidence des mécanismes suggérant l'intérêt d'un traitement à base d'anticorps monoclonaux anti-CD3
Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiological regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent TCR signaling has anti-leukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ε chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of TCR-expressing T-ALL patients and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.