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Grant support

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.

Analysis of institutional authors

Valero JgAuthorMatas-Céspedes AAuthorArenas FAuthorRodríguez VAuthorSerrat NAuthorGuerrero-Hernández MAuthorBalagué OAuthorMartin SAuthorCapdevila CAuthorHernandez, LAuthorMagnano LAuthorRivas-Delgado AAuthorCid McAuthorCampo EAuthorLópez-Guillermo AAuthorColomer DAuthorPérez-Galán PCorresponding Author

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March 22, 2021
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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

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

Authors: 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

Affiliations

‎ AstraZeneca, BioPharmaceut R&D, Clin Pharmacol & Safety Sci, Cambridge, England - Author
‎ Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain - Author
‎ Garvan Inst Med Res, Sydney, NSW, Australia - Author
‎ Gilead Sci Inc, Foster City, CA USA - Author
‎ Hosp Clin IDIBAPS, Dept Hematol, Barcelona, Spain - Author
‎ IDIBAPS, Dept Hematol Oncol, Barcelona, Spain - Author
‎ IDIBAPS, Hosp Clinic, Pathol Dept, Hematopathol Unit, Barcelona, Spain - Author
‎ Stem Cells & Canc Ctr Genom Regulat CRG PRBB, Dept Gene Regulat, Barcelona, Spain - Author
‎ Tokai Univ, Dept Pathol, Sch Med, Isehara, Kanagawa, Japan - Author
‎ Univ Barcelona, Hosp Clin, Dept Autoimmune Dis, IDIBAPS, Barcelona, Spain - Author
‎ Univ Barcelona, Med Sch, Barcelona, Spain - Author
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Abstract

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.

Keywords

AminopyridinesAnimalsApoptosisBiomarkers, tumorCell differentiationCell proliferationGene expression regulation, neoplasticHumansLymphoma, follicularMacrophagesMiceMonocytesPexidartinibPhosphorylationPyrrolesReceptor, macrophage colony-stimulating factorTumor cells, culturedTumor microenvironmentXenograft model antitumor assays

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Leukemia due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 7/78, thus managing to position itself as a Q1 (Primer Cuartil), in the category Hematology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.99. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.19 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 17.74 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-24, the following number of citations:

  • WoS: 44
  • Scopus: 41
  • Europe PMC: 36

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-24:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 50.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 51 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 7.75.
  • The number of mentions on the social network X (formerly Twitter): 10 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Australia; Japan; United Kingdom; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (García Valero, Juan) and Last Author (Pérez Galán, Patricia).

the author responsible for correspondence tasks has been Pérez Galán, Patricia.