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

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-dependen...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9643439/
https://www.ncbi.nlm.nih.gov/pubmed/36347876
http://dx.doi.org/10.1038/s41467-022-34548-3
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author 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
author_facet 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
author_sort Allouch, Awatef
collection PubMed
description 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.
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spelling pubmed-96434392022-11-14 CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia 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 Nat Commun Article 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. Nature Publishing Group UK 2022-11-08 /pmc/articles/PMC9643439/ /pubmed/36347876 http://dx.doi.org/10.1038/s41467-022-34548-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
title CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
title_full CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
title_fullStr CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
title_full_unstemmed CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
title_short CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
title_sort cdkn1a is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9643439/
https://www.ncbi.nlm.nih.gov/pubmed/36347876
http://dx.doi.org/10.1038/s41467-022-34548-3
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