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We thank Ariadna Giro for her technical assistance, Dr. Giovanna Roncador for sharing CSF-1R antibody and for technical advice, Dr. YS Choi for sharing HK cells, the IDIBAPS genomics facility for gene expression data generation and the IDIBAPS tumor bank for IHC performance. We are indebted to the HCB-IDIBAPS Biobank, integrated in the Spanish National Biobanks Network, for the biological human samples and data procurement. This work was carried out at the Esther Koplowitz Center, Barcelona. Grants that contributed to this work included: Gilead Sciences Research Funded Agreement, Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) Una manera de hacer Europa for SAF2014/57708R and SAF2017/88275R to PP-G and MCC, RTI2018-094584-B-I00 to DC, CIBERONC (CB16/12/00334 and CB16/12/00225), and finally Generalitat de Catalunya support for AGAUR 2017SGR1009 to DC.

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

Publicat a:Leukemia. 35 (9): 2635-2649 - 2021-09-01 35(9), DOI: 10.1038/s41375-021-01201-9

Autors: Valero, Juan Garcia; Matas-Cespedes, Alba; Arenas, Fabian; Rodriguez, Vanina; Carreras, Joaquim; Serrat, Neus; Guerrero-Hernandez, Martina; Yahiaoui, Anella; Balague, Olga; Martin, Silvia; Capdevila, Cristina; Hernandez, Lluis; Magnano, Laura; Rivas-Delgado, Alfredo; Tannheimer, Stacey; Cid, Maria C; Campo, Elias; Lopez-Guillermo, Armando; Colomer, Dolors; Perez-Galan, Patricia

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Resum

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.

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