Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is the main cause of mortality among hematologic diseases in Western nations. B-CLL is correlated with an intense alteration of the immune system. The altered functions of innate immune elements and adaptive immune factors are interconnected in B-CLL and are decisive for its onset, evolution, and therapeutic response. Modifications in the cytokine balance could support the growth of the leukemic clone via a modulation of cellular proliferation and apoptosis, as some cytokines have been reported to be able to affect the life of B-CLL cells in vivo. In this review, we will examine the role played by cytokines in the cellular dynamics of B-CLL patients, interpret the contradictions sometimes present in the literature regarding their action, and evaluate the possibility of manipulating their production in order to intervene in the natural history of the disease.

Keywords: B lymphocyte; T lymphocyte; chronic lymphocytic leukemia; cytokine; immune system.

Figure 1

Graphic overview of the mechanisms of cytokine involvement in B-cell lymphocytic leukemia (B-CLL) cellular dynamics (blue arrows: effects of immune cells on B-CLL cells; red arrows: B-CLL cell responses). Cytokines in plain text are those involved in the effects on B-CLL cells (blue: signaling; red: immunosuppression; gold: survival; gray: proliferation); cytokines in italics are those involved in the B-CLL cell response (green: expansion; orange: exhaustion; black: chemoattraction; red: immunosuppression; blue: pro-tumor skewing; gray: immune evasion). CCL: chemokine (C-C motif) ligand; CD38: Custer of Differentiation; IL: Interleukin PD-1: Programmed cell death protein 1; MIF: Macrophage migration inhibitory factor; CCR-2: C-C chemokine receptor type 2; NAMPT: Nicotinamide phosphoribosyltransferase; HMGB: High Mobility Group Box; CXCL: chemokine (C-X-C motif) ligand; BAFF: B-Cell Activating Factor; TNF: Tumour Necrosis Factor.

Figure 2

Clusters of identified cytokines, their respective interplay, and their impact on Chronic lymphocytic leukemia (CLL) prognosis. CL: Cluster; IFN: interferon; GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor.