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Lymphoma

CSF1R and BTK inhibitions as novel strategies to disrupt the dialog between mantle cell lymphoma and macrophages

Abstract

The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation, and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. Here, we focused on the interplay between MCL cells and the associated monocytes/macrophages. Using circulating MCL cells (n = 58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163+ M2-like macrophages (MϕMCL). In turn, MϕMCL favored lymphoma survival and proliferation ex vivo. We next demonstrated that BTK inhibition abrogated CSF1 and IL-10 production in MCL cells, leading to the inhibition of macrophage polarization and consequently resulting in the suppression of microenvironment-dependent MCL expansion. In vivo, we showed that CSF1 and IL-10 plasma concentrations were higher in MCL patients than in healthy donors, and that monocytes from MCL patients overexpressed CD163. Further analyses of serial samples from ibrutinib-treated patients (n = 8) highlighted a rapid decrease of CSF1, IL-10, and CD163 in responsive patients. Finally, we showed that targeting the CSF1R abrogated MϕMCL-dependent MCL survival, irrespective of their sensitivity to ibrutinib. These data reinforced the role of the microenvironment in lymphoma and suggested that macrophages are a potential target for developing novel therapeutic strategies in MCL.

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Acknowledgements

This study was supported by la Ligue Contre le Cancer Grand-Ouest, i-Site NexT (ANR-16-IDEX-0007), and the SIRIC ILIAD (INCa-DGOS-Inserm_12558). We thank Janssen-Cilag and Roche for supporting in part this study. The authors thank Elise Douillard (CRCINA) for excellent technical expertise. BT is the recipient for a fellowship from Fondation ARC.

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AP designed and performed experiments, analyzed data, and wrote the article. BT participated in bioinformatics analysis. CB performed experiments and participated in bioinformatics analysis. AM provided biopsy samples and analyzed data. YLB provided samples. HM provided samples. PM participated in the design of the study. CT provided samples. MA participated in the design of the study and reviewed the article. CPD participated in the design of the study, in the data analysis, and in the writing of the article. SLG participated in the design of the study, in the data analysis, and in the writing of the article. DC designed and performed experiments, analyzed data, and wrote the article.

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Correspondence to David Chiron.

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SLG is a consultant/advisory board member and has received an honorarium from Roche and Janssen-Cilag. The remaining authors declare that they have no conflict of interest.

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Papin, A., Tessoulin, B., Bellanger, C. et al. CSF1R and BTK inhibitions as novel strategies to disrupt the dialog between mantle cell lymphoma and macrophages. Leukemia 33, 2442–2453 (2019). https://doi.org/10.1038/s41375-019-0463-3

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