CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells

Relapse is a major issue in acute myeloid leukemia (AML) and while the contribution of gene mutations in developing drug resistance is well established, little is known on the role of macrophages (MΦs) in an AML cell microenvironment. We examined whether myeloblasts could educate MΦs to adopt a prot...

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Autores principales:	Tatiana Smirnova, Caroline Spertini, Olivier Spertini
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	AML macrophages M-CSF CSF1 receptor GM-CSF CD163 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f8559ad842584c5081042b14eb85a8b8
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spelling	oai:doaj.org-article:f8559ad842584c5081042b14eb85a8b82021-11-11T15:27:20ZCSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells10.3390/cancers132152892072-6694https://doaj.org/article/f8559ad842584c5081042b14eb85a8b82021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5289https://doaj.org/toc/2072-6694Relapse is a major issue in acute myeloid leukemia (AML) and while the contribution of gene mutations in developing drug resistance is well established, little is known on the role of macrophages (MΦs) in an AML cell microenvironment. We examined whether myeloblasts could educate MΦs to adopt a protumoral orientation supporting myeloblast survival and resistance to therapy. Flow cytometry analyses demonstrated that M2-like CD163<sup>+</sup> MΦs are abundantly present, at diagnosis, in the bone marrow of AML patients. We showed that myeloblasts, or their conditioned medium, polarize monocytes to M2-like CD163<sup>+</sup> MΦs, induce the secretion of many protumoral factors, and promote myeloblast survival and proliferation as long as close intercellular contacts are maintained. Importantly, pharmacologic inhibition of the CSF1 receptor (CSF1R), in the presence of GM-CSF, reprogrammed MΦ polarization to an M1-like orientation, induced the secretion of soluble factors with antitumoral activities, reduced protumoral agonists, and promoted the apoptosis of myeloblasts interacting with MΦs. Furthermore, myeloblasts, which became resistant to venetoclax or midostaurin during their interplay with protumoral CD163<sup>+</sup> MΦs, regained sensitivity to these targeted therapies following CSF1R inhibition in the presence of GM-CSF. These data reveal a crucial role of CD163<sup>+</sup> MΦ interactions with myeloblasts that promote myeloblast survival and identify CSF1R inhibition as a novel target for AML therapy.Tatiana SmirnovaCaroline SpertiniOlivier SpertiniMDPI AGarticleAMLmacrophagesM-CSFCSF1 receptorGM-CSFCD163Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5289, p 5289 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AML macrophages M-CSF CSF1 receptor GM-CSF CD163 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	AML macrophages M-CSF CSF1 receptor GM-CSF CD163 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Tatiana Smirnova Caroline Spertini Olivier Spertini CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
description	Relapse is a major issue in acute myeloid leukemia (AML) and while the contribution of gene mutations in developing drug resistance is well established, little is known on the role of macrophages (MΦs) in an AML cell microenvironment. We examined whether myeloblasts could educate MΦs to adopt a protumoral orientation supporting myeloblast survival and resistance to therapy. Flow cytometry analyses demonstrated that M2-like CD163<sup>+</sup> MΦs are abundantly present, at diagnosis, in the bone marrow of AML patients. We showed that myeloblasts, or their conditioned medium, polarize monocytes to M2-like CD163<sup>+</sup> MΦs, induce the secretion of many protumoral factors, and promote myeloblast survival and proliferation as long as close intercellular contacts are maintained. Importantly, pharmacologic inhibition of the CSF1 receptor (CSF1R), in the presence of GM-CSF, reprogrammed MΦ polarization to an M1-like orientation, induced the secretion of soluble factors with antitumoral activities, reduced protumoral agonists, and promoted the apoptosis of myeloblasts interacting with MΦs. Furthermore, myeloblasts, which became resistant to venetoclax or midostaurin during their interplay with protumoral CD163<sup>+</sup> MΦs, regained sensitivity to these targeted therapies following CSF1R inhibition in the presence of GM-CSF. These data reveal a crucial role of CD163<sup>+</sup> MΦ interactions with myeloblasts that promote myeloblast survival and identify CSF1R inhibition as a novel target for AML therapy.
format	article
author	Tatiana Smirnova Caroline Spertini Olivier Spertini
author_facet	Tatiana Smirnova Caroline Spertini Olivier Spertini
author_sort	Tatiana Smirnova
title	CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
title_short	CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
title_full	CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
title_fullStr	CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
title_full_unstemmed	CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells
title_sort	csf1r inhibition combined with gm-csf reprograms macrophages and disrupts protumoral interplays with aml cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f8559ad842584c5081042b14eb85a8b8
work_keys_str_mv	AT tatianasmirnova csf1rinhibitioncombinedwithgmcsfreprogramsmacrophagesanddisruptsprotumoralinterplayswithamlcells AT carolinespertini csf1rinhibitioncombinedwithgmcsfreprogramsmacrophagesanddisruptsprotumoralinterplayswithamlcells AT olivierspertini csf1rinhibitioncombinedwithgmcsfreprogramsmacrophagesanddisruptsprotumoralinterplayswithamlcells
_version_	1718435281055514624

CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells

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