(d) PBMCs from CLL individuals (= 4) were cultured with lenalidomide (1? 0.05; Mann-WhitneyUtest). The recognition of leukemia cells by NK cells may be increased by using antileukemic monoclonal antibodies [7, 8]. cells from CLL sufferers. Lenalidomide upregulated Compact disc20 appearance on leukemia cells and in addition, accordingly, it acquired a synergistic impact with rituximab on marketing antibody-dependent cell-mediated cytotoxicity against principal leukemia cells. General, a support is supplied by these observations for merging lenalidomide with rituximab as cure in CLL. 1. Launch Chronic lymphocytic leukemia (CLL) is normally a heterogeneous disease, using a scientific presentation which range from indolent to advanced stage disease. A healing involvement is necessary in sufferers with indolent disease scarcely, whereas chemotherapy treatment is necessary in sufferers with advanced stage disease frequently. However, CLL is recognized as an incurable disease and generally, consequently, the introduction of brand-new Luseogliflozin therapeutic strategies is normally a key objective within this malignancy [1]. Increasing proof demonstrates which the tumor microenvironment has a crucial function in CLL therapy and development performance. The disease fighting capability can prevent cancer advancement, either through the elimination of cancer tumor cells ahead of tumors getting medically detectable or by attenuating tumor development [2, 3]. NK and T cells may mediate antitumor responses, particularly in the initial stages of the disease, which may impact disease progression [4, 5]. However, advanced disease patients develop multiple immune defects, including hypogammaglobulinemia, deregulation of the cytokine network, or impairment of T and NK cells function [6]. Nevertheless, targeting the immune system may represent a encouraging therapeutic strategy in CLL. Thus, chemotherapy is usually often combined with an anti-CD20 monoclonal antibody (rituximab) in patients with advanced stage disease, resulting in enhanced total and overall response rates. The relevant mechanism of action of rituximab is the activation of NK cell-dependent antibody-dependent cell-mediated cytotoxicity (ADCC) against leukemia Luseogliflozin cells [7, 8]. Lenalidomide (Revlimid; Celgene) is an immunomodulatory drug that has shown a clinical effect in several hematological disorders including myeloma [9], myelodysplastic syndrome (MDS) [10], and CLL [11C14]. Lenalidomide displays a number of pharmacodynamic effects, but the main mechanism of action is not completely known and may vary depending on the disease. In multiple myeloma, lenalidomide exerts a direct cytotoxic effect on neoplastic plasma cells, inhibits cell adhesion, and induces changes in the bone marrow microenvironment [15]. In del(5q)MDS, lenalidomide directly affects erythroid progenitors [16]. In CLL, significant clinical responses, including molecular total remissions in greatly pretreated patients, have been observed [12, 14]. It Luseogliflozin is noteworthy that lenalidomide does not directly induce the apoptosis of leukemic cells [17], but it regulates crucial prosurvival and angiogenic cytokines (including IL-2, PDGF, and VEGF). Lenalidomide also stimulates antigen presentation, proliferation, and effector activity of T cells [18, 19] and may activate a minor cytotoxic populace of T cells known as invariant or CD1d-restricted NKT cells [20, 21]. Furthermore, CLL cells incubated with healthy T cells inhibit immune synapse formation, where it is restored by lenalidomide treatment [22]. Additionally, lenalidomide increases NK cell proliferation, Luseogliflozin which correlates with clinical response [11, 23, 24] and augments NK cell-mediated ADCC against tumor cells [25, 26]. Similarly, clinical responses in CLL patients treated with lenalidomide correlated with a tumor flare reaction [18], which appears to be Ctsb characteristic of this disease and may reflect Luseogliflozin a clinical manifestation of the enhancement of the immunogenic potential of tumors [14, 27]. The efficacy of lenalidomide in different malignant conditions may be explained by the presence of multiple mechanisms of action, different immune status, and specific pathogenesis of the disease. Unraveling the relevant mechanism of action is essential to optimize the treatment of patients and to develop.