Abstract
The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO). Given the morphologic and functional similarities between normal and CLL B-cell expansion in SLO, we hypothesized that CXCL13 plasma concentrations would correlate with CLL disease activity and progression. We analyzed CXCL13 plasma concentrations in 400 CLL patients and correlated the findings with other prognostic markers, time to treatment (TTT), CCL3 and CCL4 plasma concentrations, and in vivo CLL cell proliferation. We found that CXCL13 plasma concentrations were higher in CLL patients with active and advanced stage disease, resulting in a significantly shorter TTT. Accordingly, high CXCL13 levels correlated with other markers of disease activity and CCL3 levels. Higher CLL cell birth rates in vivo also associated with higher CXCL13 plasma concentrations. Interestingly, elevated CXCL13 plasma levels normalized during ibrutinib therapy, and increased in ibrutinib resistance patients. Collectively, these studies emphasize the importance of CXCL13 in crosstalk between CLL cells and the SLO microenvironment.
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References
Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev. 2018;18:148–67.
Stein H, Bonk A, Tolksdorf G, Lennert K, Rodt H, Gerdes J. Immunohistologic analysis of the organization of normal lymphoid tissue and non-Hodgkin’s lymphomas. J Histochem Cytochem. 1980;28:746–60.
Patten PE, Buggins AG, Richards J, Wotherspoon A, Salisbury J, Mufti GJ, et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood. 2008;111:5173–81.
Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563–74.
Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity. 2006;25:989–1001.
Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol. 2004;5:943–52.
Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, Kosco-Vilbois MH, et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature. 2007;446:83–7.
Allen CD, Okada T, Tang HL, Cyster JG. Imaging of germinal center selection events during affinity maturation. Science. 2007;315:528–31.
Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000;406:309–14.
Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57.
Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008;9:54–62.
Mueller SN, Germain RN. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol. 2009;9:618–29.
Saez de Guinoa J, Barrio L, Mellado M, Carrasco YR. CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics. Blood. 2011;118:1560–9.
Havenar-Daughton C, Lindqvist M, Heit A, Wu JE, Reiss SM, Kendric K, et al. CXCL13 is a plasma biomarker of germinal center activity. Proc Natl Acad Sci USA. 2016;113:2702–7.
Mehraj V, Ramendra R, Isnard S, Dupuy FP, Lebouche B, Costiniuk C, et al. CXCL13 as a biomarker of immune activation during early and chronic HIV infection. Front Immunol. 2019;10:289.
Burkle A, Niedermeier M, Schmitt-Graff A, Wierda WG, Keating MJ, Burger JA. Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. Blood. 2007;110:3316–25.
Durig J, Schmucker U, Duhrsen U. Differential expression of chemokine receptors in B cell malignancies. Leukemia. 2001;15:752–6.
Lopez-Giral S, Quintana NE, Cabrerizo M, Alfonso-Perez M, Sala-Valdes M, De Soria VG, et al. Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination. J Leukoc Biol. 2004;76:462–71.
Trentin L, Cabrelle A, Facco M, Carollo D, Miorin M, Tosoni A, et al. Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood. 2004;104:502–8.
Stache V, Verlaat L, Gatjen M, Heinig K, Westermann J, Rehm A, et al. The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival. Oncoimmunology. 2017;6:e1323155.
Burger JA, Quiroga MP, Hartmann E, Burkle A, Wierda WG, Keating MJ, et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood. 2009;113:3050–8.
Hartmann EM, Rudelius M, Burger JA, Rosenwald A. CCL3 chemokine expression by chronic lymphocytic leukemia cells orchestrates the composition of the microenvironment in lymph node infiltrates. Leuk Lymphoma. 2016;57:563–71.
Benet ZL, Marthi M, Ke F, Wu R, Turner JS, Gabayre JB, et al. CCL3 promotes germinal center B cells sampling by follicular regulatory T cells in murine lymph nodes. Front Immunol. 2018;9:2044.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.
Burger JA, Li KW, Keating MJ, Sivina M, Amer AM, Garg N, et al. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib. JCI insight. 2017;2:e89904.
Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity. 2000;12:471–81.
Lee HT, Shiao YM, Wu TH, Chen WS, Hsu YH, Tsai SF, et al. Serum BLC/CXCL13 concentrations and renal expression of CXCL13/CXCR5 in patients with systemic lupus erythematosus and lupus nephritis. J Rheumatol. 2010;37:45–52.
Finch DK, Ettinger R, Karnell JL, Herbst R, Sleeman MA. Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease. Eur J Clin Investig. 2013;43:501–9.
Herndon TM, Chen SS, Saba NS, Valdez J, Emson C, Gatmaitan M, et al. Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood. Leukemia. 2017;31:1340–7.
Niemann CU, Herman SE, Maric I, Gomez-Rodriguez J, Biancotto A, Chang BY, et al. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib-findings from an investigator-initiated phase II study. Clin Cancer Res. 2016;22:1572–82.
Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017;129:1469–79.
Heinig K, Gatjen M, Grau M, Stache V, Anagnostopoulos I, Gerlach K, et al. Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation. Cancer Discov. 2014;4:1448–65.
Farinello D, Wozinska M, Lenti E, Genovese L, Bianchessi S, Migliori E, et al. A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression. Nat Commun. 2018;9:1787.
Acknowledgements
The authors are grateful to all the patients who provided samples for this study. We thank Claire Pacelli for assistance with tissue bank. This work was supported by MD Anderson’s CLL Moonshot program (JAB), and in part by the MD Anderson Cancer Center Support Grant CA016672.
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MS performed chemokine measurements, collected clinical information, analyzed the data and results, designed the figures, and wrote the paper. LX and XH performed the statistical analysis and assisted with the data interpretation. EK and AV contributed with sample collection and storage. S-SC and NC analyzed birth rate data. MJK, AF, ZE, NJ, and WGW contributed to clinical patient management. JAB designed and supervised the study, and wrote the paper together with MS. All authors reviewed the manuscript and approved the final version.
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JAB, NJ, and WGW received research funding from Pharmacyclics, an AbbVie company. The remaining authors declared no competing financial interests.
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Sivina, M., Xiao, L., Kim, E. et al. CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia. Leukemia 35, 1610–1620 (2021). https://doi.org/10.1038/s41375-020-01063-7
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DOI: https://doi.org/10.1038/s41375-020-01063-7
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