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

Juan García Valero ,Alba Matas-Céspedes,Martina Guerrero-Hernández,Fabián Arenas,Olga Balagué,Patricia Pérez-Galán,Vanina Rodríguez ,Laura Magnano,Silvia Martín ,Stacey Tannheimer,Anella Yahiaoui,Alfredo Rivas‐Delgado ,Armando López‐Guillermo ,Joaquim Carreras,María C Cid ,Lluís Hernández ,Cristina Capdevila,Elı́as Campo ,Neus Serrat,Dolors Colomer

doi:10.1038/s41375-021-01201-9

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.

Highlights

Using primary follicular lymphoma (FL)-follicular dendritic cells (FDC) co-cultures to mimic the germinal center (GC) ex vivo and in vivo, we have demonstrated that FL-FDC niche orchestrates the recruitment and differentiation of monocyte to macrophages and their polarization into M2like tumor associated macrophages (TAMs), which support FL survival, angiogenesis, and dissemination
We first acknowledged that supernatants of FL-FDC cocultures were enriched in the monocyte chemo attractant CCL2, and in the pivotal cytokine for monocyte activation and differentiation colony-stimulating factor-1 (CSF-1), compared to the supernatants of FL or HK cells in monoculture (Fig. 1A)
Monocytes from healthy donors were put in direct contact with FL cell lines (FL-CL) and primary cells from FL patients (FL)

Summary

Introduction

Subsequent immunohistochemical studies tried to transfer these findings into the clinical laboratory by associating the cellular composition of the microenvironment and its spatial distribution with the progression of the disease [7] In this regard, the contribution of monocytes and macrophages to FL pathogenesis and the possible identification of suitable biomarkers with the potential to stratify FL patients remains a matter of debate [8,9,10]. This is likely due to the inherent complexity and plasticity of these cells subjected to microenvironmental cues that dictate their phenotype and function [11] Despite these controversies in FL, it is remarkable that in other hematologic neoplasia such as Hodgkin lymphoma [12], and many solid tumors [13], macrophages have been linked to disease onset and/or progression. This observation sparked an interest to therapeutically target these plastic innate immune cells [14]

Methods

Results

Conclusion