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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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References

  1. Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125:48–55.

    Article  CAS  PubMed  Google Scholar 

  2. Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. 2012;122:3416–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weisenburger DD, Armitage JO. Mantle cell lymphoma—an entity comes of age. Blood. 1996;87:4483–94.

    CAS  PubMed  Google Scholar 

  4. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018;131:2283–96.

    Article  CAS  PubMed  Google Scholar 

  6. Delfau-Larue M-H, Klapper W, Berger F, Jardin F, Briere J, Salles G, et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126:604–11.

    Article  CAS  PubMed  Google Scholar 

  7. Beà S, Valdés-Mas R, Navarro A, Salaverria I, Martín-Garcia D, Jares P, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 2013;110:18250–5.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Queirós AC, Beekman R, Vilarrasa-Blasi R, Duran-Ferrer M, Clot G, Merkel A, et al. Decoding the DNA methylome of mantle cell lymphoma in the light of the entire B cell lineage. Cancer Cell. 2016;30:806–21.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Burger JA, Gribben JG. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol. 2014;24:71–81.

    Article  CAS  PubMed  Google Scholar 

  10. Amé-Thomas P, Tarte K. The yin and the yang of follicular lymphoma cell niches: role of microenvironment heterogeneity and plasticity. Semin Cancer Biol. 2014;24:23–32.

    Article  PubMed  Google Scholar 

  11. Papin A, Le Gouill S, Chiron D. Rationale for targeting tumor cells in their microenvironment for mantle cell lymphoma treatment. Leuk Lymphoma. 2017;59:1064–72.

    Article  Google Scholar 

  12. Chiron D, Bellanger C, Papin A, Tessoulin B, Dousset C, Maiga S. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood. 2016;128:2808–18.

    Article  CAS  PubMed  Google Scholar 

  13. Saba NS, Liu D, Herman SEM, Underbayev C, Tian X, Behrend D, et al. Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma. Blood. 2016;128:82–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen Z, Teo AE, McCarty N. ROS-induced CXCR4 signaling regulates mantle cell lymphoma (MCL) cell survival and drug resistance in the bone marrow microenvironment via autophagy. Clin Cancer Res. 2016;22:187–99.

    Article  CAS  PubMed  Google Scholar 

  15. Chiron D, Dousset C, Brosseau C, Touzeau C, Maïga S, Moreau P, et al. Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget. 2015;6:8750–9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113:4604–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Amin R, Mourcin F, Uhel F, Pangault C, Ruminy P, Dupré L, et al. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood. 2015;126:1911–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nguyen P-H, Fedorchenko O, Rosen N, Koch M, Barthel R, Winarski T, et al. LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia. Cancer Cell. 2016;30:610–22.

    Article  CAS  PubMed  Google Scholar 

  22. Galletti G, Scielzo C, Barbaglio F, Rodriguez TV, Riba M, Lazarevic D, et al. Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression. Cell Rep. 2016;14:1748–60.

    Article  CAS  PubMed  Google Scholar 

  23. Song K, Herzog BH, Sheng M, Fu J, McDaniel JM, Chen H, et al. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma. Cancer Res. 2013;73:7254–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pham LV, Vang MT, Tamayo AT, Lu G, Challagundla P, Jorgensen JL, et al. Involvement of tumor-associated macrophage activation in vitro during development of a novel mantle cell lymphoma cell line, PF-1, derived from a typical patient with relapsed disease. Leuk Lymphoma. 2015;56:186–93.

    Article  CAS  PubMed  Google Scholar 

  25. Hanf M, Chiron D, de Visme S, Touzeau C, Maisonneuve H, Jardel H, et al. The REFRACT-LYMA cohort study: a French observational prospective cohort study of patients with mantle cell lymphoma. BMC Cancer [Internet]. 2016;16:802. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064959/

    Article  Google Scholar 

  26. Derlindati E, Dei Cas A, Montanini B, Spigoni V, Curella V, Aldigeri R, et al. Transcriptomic analysis of human polarized macrophages: more than one role of alternative activation? PLoS One. 2015;10:e0119751.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Maïga S, Brosseau C, Descamps G, Dousset C, Gomez-Bougie P, Chiron D, et al. A simple flow cytometry-based barcode for routine authentication of multiple myeloma and mantle cell lymphoma cell lines. Cytometry A. 2015;87:285–8.

    Article  PubMed  Google Scholar 

  29. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.

    Article  CAS  PubMed  Google Scholar 

  31. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vishwamitra D, Shi P, Wilson D, Manshouri R, Vega F, Schlette EJ, et al. Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma. Haematologica. 2011;96:871–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Baran-Marszak F, Boukhiar M, Harel S, Laguillier C, Roger C, Gressin R, et al. Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma. Haematologica. 2010;95:1865–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang L, Yang J, Qian J, Li H, Romaguera JE, Kwak LW, et al. Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells. Blood. 2012;120:3783–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili S-A, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233:6425–40.

    Article  CAS  PubMed  Google Scholar 

  36. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yeh Y-M, Hsu S-J, Lin P-C, Hsu K-F, Wu P-Y, Su W-C, et al. The c.1085A>G genetic variant of CSF1R gene regulates tumor immunity by altering the proliferation, polarization, and function of macrophages. Clin Cancer Res. 2017;23:6021–30.

    Article  CAS  PubMed  Google Scholar 

  38. Edwards DK, Watanabe-Smith K, Rofelty A, Damnernsawad A, Laderas T, Lamble A, et al. CSF1R inhibitors exhibit anti-tumor activity in acute myeloid leukemia by blocking paracrine signals from support cells. Blood. 2018;133:588–99

    Article  PubMed  Google Scholar 

  39. Bernard S, Danglade D, Gardano L, Laguillier C, Lazarian G, Roger C, et al. Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma. Int J Cancer. 2015;136:2761–74.

    Article  CAS  PubMed  Google Scholar 

  40. Chang BY, Francesco M, De Rooij MFM, Magadala P, Steggerda SM, Huang MM, et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122:2412–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rahal R, Frick M, Romero R, Korn JM, Kridel R, Chan FC, et al. Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014;20:87–92.

    Article  CAS  PubMed  Google Scholar 

  42. Zhao X, Lwin T, Silva A, Shah B, Tao J, Fang B, et al. Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun. 2017;8:14920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 2012;33:119–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat Rev Drug Discov. 2016;16:53–70.

    Article  PubMed  Google Scholar 

  45. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846–59.

    Article  CAS  PubMed  Google Scholar 

  46. Zhu X-D, Zhang J-B, Zhuang P-Y, Zhu H-G, Zhang W, Xiong Y-Q, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26:2707–16.

    Article  PubMed  Google Scholar 

  47. Polk A, Lu Y, Wang T, Seymour E, Bailey NG, Singer JW, et al. Colony-stimulating factor-1 receptor is required for nurse-like cell survival in chronic lymphocytic leukemia. Clin Cancer Res. 2016;22:6118–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gutiérrez-González A, Martínez-Moreno M, Samaniego R, Arellano-Sánchez N, Salinas-Muñoz L, Relloso M, et al. Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma. Blood. 2016;128:2241–52.

    Article  PubMed  Google Scholar 

  50. Moughon DL, He H, Schokrpur S, Jiang ZK, Yaqoob M, David J, et al. Macrophage blockade using CSF1R inhibitors reverses the vascular leakage underlying malignant ascites in late-stage epithelial ovarian cancer. Cancer Res. 2015;75:4742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood. 2010;115:1461–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen JG, Liu X, Munshi M, Xu L, Tsakmaklis N, Demos MG, et al. BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism. Blood. 2018;131:2047–59.

    Article  CAS  PubMed  Google Scholar 

  53. Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Martin P, Maddocks K, Leonard JP, Ruan J, Goy A, Wagner-Johnston N, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559–63.

    Article  CAS  PubMed  Google Scholar 

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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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