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

Awatef Allouch (1) , Laurent Voisin (1) , Yanyan Zhang , Syed Qasim Raza (1) , Yann Lecluse , Julien Calvo , Dorothée Selimoglu-Buet , Stéphane de Botton (2, 3) , Fawzia Louache , Françoise Pflumio , Éric Solary (4, 5) , Jean-Luc Perfettini (1, 2)

1 RaMo-IT - Radiothérapie Moléculaire et Innovation Thérapeutique
2 IGR - Institut Gustave Roussy
3 Département d'hématologie [Gustave Roussy]
4 U1170 Inserm - Hématopoïèse normale et pathologique
5 CSHMyelo - U1287 Inserm - Cellules souches hématopoïétiques et développement des hémopathies myéloïdes

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.

Domaines: Sciences du Vivant [q-bio]

Awatef Allouch, Laurent Voisin, Yanyan Zhang, Syed Qasim Raza, Yann Lecluse, et al.. CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia. Nature Communications, 2022, 13 (1), pp.6739. ⟨10.1038/s41467-022-34548-3⟩. ⟨hal-04438501⟩