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CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia

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  • Awatef Allouch

    (Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
    Gustave Roussy Cancer Center
    NH TherAguix)

  • Laurent Voisin

    (Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
    Gustave Roussy Cancer Center)

  • Yanyan Zhang

    (Gustave Roussy Cancer Center
    Inserm U955, Université Paris-Est Créteil (UPEC))

  • Syed Qasim Raza

    (Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
    Gustave Roussy Cancer Center
    University of Veterinary and Animal Sciences-UVAS)

  • Yann Lecluse

    (Gustave Roussy Cancer Center
    Université Paris-Saclay, UMS 3655 CNRS / US 23 Inserm, Imaging and Cytometry Platform)

  • Julien Calvo

    (Université de Paris, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations
    Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations
    UMR Stabilité Génétique Cellules Souches et Radiations
    The Organization for Partnerships in Leukemia, Saint-Louis Hospital)

  • Dorothée Selimoglu-Buet

    (Gustave Roussy Cancer Center
    Université Paris-Saclay, Inserm UMR1287, Hematopoietic stem cells and the development of myeloid malignancies)

  • Stéphane Botton

    (Gustave Roussy Cancer Center)

  • Fawzia Louache

    (Gustave Roussy Cancer Center
    Université Paris-Saclay, Inserm UMR-S-MD1197, Hôpital Paul Brousse)

  • Françoise Pflumio

    (Université de Paris, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations
    Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations
    UMR Stabilité Génétique Cellules Souches et Radiations
    The Organization for Partnerships in Leukemia, Saint-Louis Hospital)

  • Eric Solary

    (Gustave Roussy Cancer Center
    Université Paris-Saclay, Inserm UMR1287, Hematopoietic stem cells and the development of myeloid malignancies)

  • Jean-Luc Perfettini

    (Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
    Gustave Roussy Cancer Center)

Abstract

Targeting the reprogramming and phagocytic capacities of tumor-associated macrophages (TAMs) has emerged as a therapeutic opportunity for cancer treatment. Here, we demonstrate that tumor cell phagocytosis drives the pro-inflammatory activation of TAMs and identify a key role for the cyclin-dependent kinase inhibitor CDKN1A (p21). Through the transcriptional repression of Signal-Regularity Protein α (SIRPα), p21 promotes leukemia cell phagocytosis and, subsequently, the pro-inflammatory reprogramming of phagocytic macrophages that extends to surrounding macrophages through Interferon γ. In mouse models of human T-cell acute lymphoblastic leukemia (T-ALL), infusion of human monocytes (Mos) engineered to overexpress p21 (p21TD-Mos) leads to Mo differentiation into phagocytosis-proficient TAMs that, after leukemia cell engulfment, undergo pro-inflammatory activation and trigger the reprogramming of bystander TAMs, reducing the leukemic burden and substantially prolonging survival in mice. These results reveal p21 as a trigger of phagocytosis-guided pro-inflammatory TAM reprogramming and highlight the potential for p21TD-Mo-based cellular therapy as a cancer immunotherapy.

Suggested Citation

  • Awatef Allouch & Laurent Voisin & Yanyan Zhang & Syed Qasim Raza & Yann Lecluse & Julien Calvo & Dorothée Selimoglu-Buet & Stéphane Botton & Fawzia Louache & Françoise Pflumio & Eric Solary & Jean-Luc, 2022. "CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34548-3
    DOI: 10.1038/s41467-022-34548-3
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