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 Botton, Fawzia Louache, Françoise Pflumio, Eric Solary and Jean-Luc Perfettini ()
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Awatef Allouch: Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
Laurent Voisin: Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
Yanyan Zhang: Gustave Roussy Cancer Center
Syed Qasim Raza: Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation
Yann Lecluse: Gustave Roussy Cancer Center
Julien Calvo: Université de Paris, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations
Dorothée Selimoglu-Buet: Gustave Roussy Cancer Center
Stéphane Botton: Gustave Roussy Cancer Center
Fawzia Louache: Gustave Roussy Cancer Center
Françoise Pflumio: Université de Paris, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations
Eric Solary: Gustave Roussy Cancer Center
Jean-Luc Perfettini: Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34548-3

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