It would be interesting to understand what type of cancer (i.e. hematopoietic and/or solid organ tumors) developed in DKO mice or in the BM chimeras and which immune cells contributed to the tumor control in this setting. To more closely evaluate tumor selleck products growth in Was−/− mice and to directly study the role of different immune cells, the authors injected the mice with the B16 melanoma cell line. This model has

been extensively employed, especially to study NK-cell-mediated antitumor activity [14]. NK cells contribute to cancer immunosurveillance by perforin- and granzyme-mediated cytolytic activity toward tumor cells and by secretion of effector cytokines, especially IFN-γ. These events occur as a result of the sum of inhibitory and activating signals triggered upon engagement of NK-cell receptors with the correspondent ligands expressed by the target cell [15]. The contact between the NK cell and the tumor cell is a specialized form of IS, known as the NK-cell lytic IS, which leads to cytotoxicity of the target cell [16]. As described for the T-cell IS, an important step in the formation of the NK-cell lytic IS is the synaptic accumulation

EPZ-6438 price of filamentous actin (F-actin). In normal NK cells, WASp is expressed and localizes to the IS together with F-actin, while NK cells from WAS patients fail to accumulate F-actin and perforin at the IS and have impaired cytolytic function [17, 18]. The B16 melanoma cell line is sensitive to NK-cell-mediated killing, because B16 cells express only low levels of class I molecules

[19], which bind to NK-cell inhibitory receptors, but typical amounts of the ligands of several activating receptors, namely, NKp46, NKG2D, and DNAM-1 [20] so the activating signals dominate and lead to target/melanoma Celecoxib cell death. By subcutaneous injection of B16 cells into Was−/− and WT mice, Catucci et al. [11] observed that Was−/− mice displayed a higher volume of primary tumors and a lower infiltration of NK cells, but not total CD3+, CD8+ T cells nor CD11c+ DCs, as compared with WT mice. Similarly, intravenous injection of B16 cells into Was−/− mice resulted in a higher incidence of lung metastases, which was reduced by the adoptive transfer of WT NK cells [11]. The mechanisms underlying this phenomenon could be multiple. In Fig. 1, we try to envisage at which steps Was deficiency could impact on NK-cell-mediated tumor immunosurveillance. These effects might at least partially depend on the inability of NK cells derived from Was−/− mice to form a lytic IS with the tumor cells (Fig. 1). Moreover, WASp has also been implied in regulating the stop signal resulting after the interaction between the NK-cell activating receptor NKG2D and its ligands on the target cells [21].