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

• Published in: Leukemia 2019-10, Vol.33 (10), p.2442-2453
• Main Authors: Papin, Antonin, Tessoulin, Benoit, Bellanger, Céline, Moreau, Anne, Le Bris, Yannick, Maisonneuve, Hervé, Moreau, Philippe, Touzeau, Cyrille, Amiot, Martine, Pellat-Deceunynck, Catherine, Le Gouill, Steven, Chiron, David
• Format: Article
• Language: English
• Subjects: 13; 13/31; 38; 38/77; 631/67/1990/291/1621/1915; 631/67/327; 82; 82/80; 96/21; Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Aged; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Cancer Research; CD163 antigen; Cell Line, Tumor; Cell survival; Chemoresistance; Critical Care Medicine; Drug Resistance, Neoplasm - drug effects; Drug therapy; Enzyme inhibitors; Female; Health aspects; Hematology; Humans; Intensive; Interleukin 10; Interleukin-10 - metabolism; Internal Medicine; Lymphoma; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - metabolism; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mantle; Mantle cell lymphoma; Medicine; Medicine & Public Health; Monocytes; Monocytes - drug effects; Monocytes - metabolism; Oncology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazoles - therapeutic use; Pyrimidines - therapeutic use; Receptors, Cell Surface - metabolism; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Survival; Testing; Tumor Microenvironment - drug effects
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0463-3

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.