Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Abstract

Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic 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 T-cell receptor (TCR) signaling has antileukemic 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-affi nity selfpeptide/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 patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells. SIGNIFICANCE:T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specifi c TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. Cancer Discov; 6(9);

A TCR-switchable cell death pathway in T-ALL

“…This indicated that the strong/sustained TCR activation associated with the negatively selecting TCR- HY severely impaired leukemia maintenance. Consistent with this, stimulation of a TCR-negative cell line engineered to express the TCR-HY transgene by the DBY cognate antigen resulted in dose-dependent cell death [6]. Modern multi-agent chemotherapy has considerably improved T-ALL outcome.…”

“…We observed that co-expression of the TEL- JAK2 oncogene with a transgene encoding TCR-HY, which induces negative selection only in male mice, specifically compromised leukemia onset in males [4]. Importantly, in our new study [6], when leukemias obtained from females were transplanted in either male or female secondary recipients, only females succumbed to T-ALL. This indicated that the strong/sustained TCR activation associated with the negatively selecting TCR- HY severely impaired leukemia maintenance.…”

“…OKT3 anti-leukemic effects can result from induction of a cell-intrinsic cell death program and/or antibody-dependent cell cytotoxicity (ADCC)-type responses. The fact that LAT expression knockdown in T-ALL strongly impaired the anti-leukemic response to OKT3 shows that, at least in NSG mice, OKT3-induced TCR signaling rather than ADCC-type responses is responsible for the anti-CD3 anti-leukemic effects [6]. Thus a latent cell death program, switchable by anti-CD3ε treatment, can be induced in T-ALL, which dominates the many distinct oncogenic pathways active in different tumors (Figure 1).…”

“…Thus a latent cell death program, switchable by anti-CD3ε treatment, can be induced in T-ALL, which dominates the many distinct oncogenic pathways active in different tumors (Figure 1). We identified the transcriptional program associated with anti-CD3 treatment in T-ALL in vitro [6] and in vivo (our unpubl. obs.)…”

Activating TCR Signaling to Thwart T-ALL

“…It is thought that differences in binding strength and kinetics of activation are involved, as well as the cellular localization of TCR signaling components such as ERK ( 9 ). Such complexities suggest that manipulation of TCR signaling could have unpredictable effects on T-ALL cells, depending on signaling strength and stage of thymocyte maturation, but this issue had not been extensively studied in human T-ALL prior to the paper by Trinquand and colleagues in this issue ( 10 ).…”