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

Awatef Allouch, Laurent Voisin, Yanyan Zhang, Syed Qasim Raza, Yann Lecluse, Julien Calvo, Dorothée Selimoglu-Buet, Stéphane de Botton, Fawzia Louache, Françoise Pflumio, Eric Solary, Jean Luc Perfettini

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    5 Citations (Scopus)

    Résumé

    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.

    langue originaleAnglais
    Numéro d'article6739
    journalNature Communications
    Volume13
    Numéro de publication1
    Les DOIs
    étatPublié - 1 déc. 2022

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