PD-1 signalling defines and protects leukaemic stem cells from T cell receptor-induced cell death in T cell acute lymphoblastic leukaemia.

Document Type

Article

Publication Date

1-2023

Identifier

DOI: 10.1038/s41556-022-01050-3

Abstract

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppressed disease progression. Combination therapy using PD-1 blockade and chemotherapy substantially extended the survival of mice engrafted with mouse or human T-ALL cells. Mechanistically, PD-1+ LSCs had high NOTCH1-MYC activity for disease initiation. Furthermore, PD-1 signalling maintained quiescence and protected LSCs against T cell receptor-signal-induced apoptosis. Overall, our data highlight the hierarchy of leukaemia by identifying PD-1+ LSCs and provide a therapeutic approach for the elimination of LSCs through PD-1 blockade in T-ALL.

Journal Title

Nature cell biology

Volume

25

Issue

1

First Page

170

Last Page

182

MeSH Keywords

Humans; Mice; Animals; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Leukemia, Myeloid, Acute; Receptors, Antigen, T-Cell; T-Lymphocytes; Apoptosis; Cell Death; Stem Cells

Keywords

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Programmed Cell Death 1 Receptor; Local Neoplasm Recurrence; Acute Myeloid Leukemia; T-Cell Antigen Receptors; T-Lymphocytes; Apoptosis; Cell Death; Stem Cells

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