CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
Summary Most tumor-associated macrophages (TAMs), which are abundant in the tumor microenvironment, demonstrate an immunosuppressive phenotype and contribute to tumor progression, treatment resistance and poor clinical outcomes1,2. Due to their functional plasticity, these cells could be reprogrammed to acquire a pro-inflammatory phenotype and promote tumor clearance1. Several therapeutic approaches targeting TAMs to alleviate their immunosuppressive properties or to harness their tumoricidal capacities have been developed3,4. Inhibition of interactions between phagocytic inhibitor receptors on macrophages and “don’t eat me signals” on cancer cells, which promotes cancer cell engulfment, showed therapeutic benefits for several tumor types4–6. Investigating mechanisms involved in macrophage-mediated phagocytosis of tumor cells, we demonstrate here a key role for the cyclin-dependent kinase inhibitor CDKN1A (p21). Through transcriptional repression of SIRPα (Signal-Regularity Protein α), which encodes a phagocytic inhibitor, CDKN1A promotes the ability of monocyte-derived macrophages (MDMs) to engulf leukemic cells. In turn, these MDMs acquire a pro-inflammatory phenotype that extends to surrounding MDMs in an Interferon γ (IFNγ)-dependent manner. Human monocytes genetically engineered to overexpress p21 (p21TD-Mo) differentiate into anti-inflammatory MDMs that are primed for leukemic cell phagocytosis when transferred into mice xenografted with patient-derived T-cell acute lymphoblastic leukemia (T-ALL) cells. After leukemic cell engulfment, engineered macrophages undergo a pro-inflammatory activation, reducing leukemic burden and substantially prolonging survival of mice. These results reveal p21 as a trigger of phagocytosis-guided pro-inflammatory reprogramming of TAMs and demonstrate the potential for p21TD-Mo-based cell therapy in cancer immunotherapy.
Perfettini Jean-Luc、Louache Fawzia、Pflumio Fran?oise、Voisin Laurent、De Botton St¨|phane、Calvo Julien、Lecluse Yann、Syed Raza、Allouch Awatef、Zhang Yanyan、Solary Eric、S¨|limoglu-Buet Doroth¨|e
Universit¨| Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation||Gustave Roussy Cancer Center||Department of Biomedical Sciences, University of the Pacific, Arthur A. Dugoni School of DentistryGustave Roussy Cancer Center||Universit¨| Paris-Saclay, Inserm UMR-S-MD1197, H?pital Paul BrousseInserm U1274, Team Niche and Cancer in Hematopoiesis||Commissariat ¨¤ l?ˉEnergie Atomique et aux Energies Alternatives (CEA)||Unit¨| de Recherche (UMR)-E008 Stabilit¨| G¨|n¨|tique, Cellules Souches et Radiations, Universit¨| de Paris-Universit¨| Paris-SaclayUniversit¨| Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation||Gustave Roussy Cancer CenterGustave Roussy Cancer CenterInserm U1274, Team Niche and Cancer in Hematopoiesis||Commissariat ¨¤ l?ˉEnergie Atomique et aux Energies Alternatives (CEA)||Unit¨| de Recherche (UMR)-E008 Stabilit¨| G¨|n¨|tique, Cellules Souches et Radiations, Universit¨| de Paris-Universit¨| Paris-SaclayGustave Roussy Cancer Center||Universit¨| Paris-Saclay, UMS 3655 CNRS / US 23 INSERM, Imaging and Cytometry PlatformUniversit¨| Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation||Gustave Roussy Cancer Center||Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences-UVASUniversit¨| Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation||Gustave Roussy Cancer Center||NH TherAguixGustave Roussy Cancer Center||Inserm U955, Universit¨| Paris-Est Cr¨|teil (UPEC)Gustave Roussy Cancer Center||Universit¨| Paris-Saclay, Inserm UMR1287, Hematopoietic stem cells and the development of myeloid malignanciesGustave Roussy Cancer Center||Universit¨| Paris-Saclay, Inserm UMR1287, Hematopoietic stem cells and the development of myeloid malignancies
肿瘤学基础医学分子生物学
Perfettini Jean-Luc,Louache Fawzia,Pflumio Fran?oise,Voisin Laurent,De Botton St¨|phane,Calvo Julien,Lecluse Yann,Syed Raza,Allouch Awatef,Zhang Yanyan,Solary Eric,S¨|limoglu-Buet Doroth¨|e.CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia[EB/OL].(2025-03-28)[2025-05-18].https://www.biorxiv.org/content/10.1101/2022.01.18.476736.点此复制
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