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

• Published in: Nature communications Vol. 13; no. 1; pp. 6739 - 16
• Main Authors: Allouch, Awatef, Voisin, Laurent, Zhang, Yanyan, Raza, Syed Qasim, Lecluse, Yann, Calvo, Julien, Selimoglu-Buet, Dorothée, de Botton, Stéphane, Louache, Fawzia, Pflumio, Françoise, Solary, Eric, Perfettini, Jean-Luc
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/89; 14; 14/35; 38; 38/15; 38/61; 38/88; 42; 631/250/2504/342/1726; 631/250/251; 631/61/201; 631/67/1990/283; 64/60; 96; 96/21; 96/95; Acute lymphoblastic leukemia; Animal models; Animals; Cancer; Cancer immunotherapy; Cell activation; Cell culture; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Enzyme inhibitors; Gene silencing; GTP-binding protein; Humanities and Social Sciences; Humans; Immunotherapy; Inflammation; Interferon; Kinases; Leukemia; Leukemia, Myeloid, Acute - pathology; Life Sciences; Lymphocytes T; Macrophages; Macrophages - metabolism; Mice; Monocytes; multidisciplinary; Phagocytes; Phagocytosis; Science; Science (multidisciplinary); Survival; Tumors; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34548-3

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. Inducing phagocytic capacities of tumour-associated macrophages to eliminate cancer cells is a promising immunotherapy. Here, the authors show that engineered macrophages overexpressing CDKN1A/p21 reduce leukaemic tumour burden and increase survival in preclinical mouse models of human T-ALL.