The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma.
Aminopyridines
/ pharmacology
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Differentiation
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Lymphoma, Follicular
/ drug therapy
Macrophages
/ drug effects
Mice
Monocytes
/ drug effects
Phosphorylation
Pyrroles
/ pharmacology
Receptor, Macrophage Colony-Stimulating Factor
/ antagonists & inhibitors
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
18
08
2020
accepted:
18
02
2021
revised:
03
02
2021
pubmed:
19
3
2021
medline:
6
10
2021
entrez:
18
3
2021
Statut:
ppublish
Résumé
Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures (n = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.
Identifiants
pubmed: 33731849
doi: 10.1038/s41375-021-01201-9
pii: 10.1038/s41375-021-01201-9
pmc: PMC8410584
doi:
Substances chimiques
Aminopyridines
0
Biomarkers, Tumor
0
Pyrroles
0
pexidartinib
6783M2LV5X
Receptor, Macrophage Colony-Stimulating Factor
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2635-2649Informations de copyright
© 2021. The Author(s).
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