The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma

• Published in: Leukemia 2021-09, Vol.35 (9), p.2635-2649
• Main Authors: Valero, Juan Garcia, Matas-Céspedes, Alba, Arenas, Fabián, Rodriguez, Vanina, Carreras, Joaquim, Serrat, Neus, Guerrero-Hernández, Martina, Yahiaoui, Anella, Balagué, Olga, Martin, Silvia, Capdevila, Cristina, Hernández, Lluis, Magnano, Laura, Rivas-Delgado, Alfredo, Tannheimer, Stacey, Cid, Maria C., Campo, Elías, López-Guillermo, Armando, Colomer, Dolors, Pérez-Galán, Patricia
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/31; 13/51; 45/61; 45/77; 59/5; 631/67/327; 64/60; 692/699/67/1990/291/1621/1915; 96/21; 96/63; Aminopyridines - pharmacology; Angiogenesis; Animal models; Animals; Anticancer properties; Antitumor activity; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Research; Care and treatment; CD20 antigen; Cell Differentiation; Cell Proliferation; Cell receptors; Colony-stimulating factor; Colony-stimulating factors (Physiology); Critical Care Medicine; Crosstalk; Dendritic cells; Development and progression; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Hematology; Humans; Immunosuppression; Immunotherapy; Intensive; Internal Medicine; Lymphoma; Lymphoma, Follicular - drug therapy; Lymphoma, Follicular - metabolism; Lymphoma, Follicular - pathology; Lymphomas; Macrophage colony-stimulating factor; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Medicine; Medicine & Public Health; Mice; Microenvironments; Monocyte chemoattractant protein 1; Monocytes; Monocytes - drug effects; Monocytes - metabolism; Monocytes - pathology; Oncology; Pathogenesis; Phenotypes; Phosphorylation; Polarization; Prognosis; Pyrroles - pharmacology; Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Receptor, Macrophage Colony-Stimulating Factor - genetics; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Rituximab; Survival; Therapeutic applications; Therapeutic targets; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-021-01201-9

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.