The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact

Abstract

International audienceChemokines are centrally involved in leukocyte migration, homing and haematopoiesis. Besides these physiological aspects, their role in pathological processes especially with respect to solid tumour and haematological neoplasias is well established. In this context, the focus was set here on disclosing their contribution in B cell chronic lymphocytic leukaemia (B-CLL), which is regarded as the most characteristic low-grade lymphoma. Up to now, it has been demonstrated that several chemokines are involved in migration of B-CLL cells to lymph nodes, secondary lymphoid organs and bone marrow. Moreover, some chemokines are known to have an anti-apoptotic effect and thus contribute to the survival of B-CLL cells. By interfering with both of these aspects, new therapeutic targets for this yet incurable disease may be developed. Furthermore, a correlation can be drawn between the concentration of some chemokines in patients' serum, the expression of their respective receptors on B-CLL cells and well-established predictive clinical parameters. Consequently, further systematic investigation of the chemokine network may lead to the identification of new diagnostic and prognostic markers. This review focuses on the impact of chemokines and their receptors on B-CLL pathophysiology and points out potential implications for both treatment and diagnosis

Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

“…5,17 CLL cell trafficking to sites where these stimulatory influences can be attained depends on chemokines, acting in concert with adhesion molecules. 6 Gaining a more complete understanding of the regulation of each of these pathways is essential to better understand CLL. Because the actions of certain cytokines and chemokines can be modulated by the actions of other cytokines and chemokines, identifying groups of molecules that robustly correlate with clinical course and outcome, the focus of the current work, has the potential to improve disease prognostication and may offer crucial insight into networks of signals that could be targeted by therapies.…”

“…1,2 Considerable progress has been made in understanding this cross talk, 3,4 with clinical and translational studies supporting roles for various cytokines and chemokines, together with other soluble factors, surface receptors including adhesion molecules, and antigens in the complex stimulation of leukemic cells within the microenviroment. 5,6 However, because many cytokines elevated in different CLL microenvironments are pleiotropic, with overlapping as well as antagonistic actions, determining an integrated profile of coordinately expressed cytokines that may reflect or contribute to CLL disease severity is needed. 7 Individual, specific cytokines and chemokines have been reported to be elevated in the sera, plasma, or both of CLL patients and to correlate with clinical course and outcome.…”

Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy

“…Labeled cells were cultivated in complete medium with h-IgG (10 mg/ml), RTX (10 mg/ml), or GA101 (10 mg/ml), and/or 10 ng/ml rhIL-15, for 7 d. In all experiments, CFSE dilution was analyzed on CD3 The implication of B leukemic cells as accessory cells in rhIL-15-induced NK cell proliferation was evaluated using different culture conditions: PBLs from patients (10 3 10 6 cells/ml) as control condition; purified NK cells from CLL patients (2 3 10 6 cells/ml); in a reconstituted system: a coculture of autologous purified NK and B leukemic cells (same NK/B cell ratio as in the original sample); in a Transwell system: purified NK cells at the bottom (2 3 10 6 cells/ml) and purified B leukemic cells at the top (10 3 10 6 cells/ml) (96-Multiwell Insert System; BD Biosciences); and in the presence of anti-IL-15Ra-blocking Ab (20 mg/ml; R&D Systems). In all conditions, rhIL-15 was added at a final concentration of 10 ng/ml for 7 d. Absolute NK cell number, in samples treated or not with rhIL- 15 …”

“…The accumulation of B leukemic cells depends on both cell-cell interactions (12,13) and CLL-released soluble factors (14,15). In standard therapeutic regimens, mAbs, such as rituximab (RTX), contribute largely to improve response-rate, progression-free, and overall survival of CLL patients (16).…”

FDA Approval: Idelalisib Monotherapy for the Treatment of Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma

“…PI3Kd is involved in several signaling pathways, such as the B-cell receptor, CD40, B-cell-activating factor receptor, chemokine receptors CXCR4 and CXCR5, IL6 receptor, and integrins. These pathways may be involved in B-cell proliferation, motility, and in homing to and maintenance of the tumor microenvironment in B-cell malignancies (10).…”