Mature dendritic cells (mDCs) can trigger the effector functions of natural killer (NK) cells. Knockout , small-interfering RNA or neutralizing antibodies targeting interleukin 12 (IL-12) subunits revealed a critical role for IL-12 in NK cell interferon (IFN-) secretion promoted by mDCs. However, NK cell activation by DCs also required direct cell-to-cell contacts. DC-mediated NK cell activation involved the formation of stimulatory synapses between DCs and NK cells. The formation of DC/NK cell conjugates depended on cy-toskeleton remodeling and lipid raft mobilization in DCs. Moreover, the disruption of the DC cytoskeleton using pharmaco-logic agents or the loss-of-function mutation of the Wiskott-Aldrich syndrome protein abolished the DC-mediated NK cell activation. Synapse formation promoted the polarized secretion of preassembled stores of IL-12 by DCs toward the NK cell. The synaptic delivery of IL-12 by DCs was required for IFN-secretion by NK cells, as assessed using inhibitors of cytoskel-eton rearrangements and transwell experiments. Therefore, the cross-talk between DCs and NK cells is dictated by functional synapses. (Blood. 2004;104:3267-3275) Introduction Natural killer (NK) cells recognize and kill target cells expressing virus-encoded proteins, as well as tumor cells that have lost the expression of major histocompatibility complex (MHC) class I antigens. 1-5 Activation of NK cells results from a balance between inhibitory and activating signaling pathways. 6 Incompatibilities in HLA-Cw alleles between NK and target cells promote the cytolytic function of NK cells involved in the graft-versus-leukemia reaction. 7 In contrast, receptor-ligand interactions between MHC class I molecules and killer inhibitory immunoglobulin-like receptor (KIR) or lectin-type inhibitory NK cell receptor can initiate a dominant inhibitory signaling cascade that blocks NK cell cytotoxicity. Recent studies of the physical interaction between NK cells and target cells have highlighted the functional impact of its synaptic organization. Thus, Lou et al 8 reported that, within the NK/ target cell synapse, lipid rafts polarized to the site of the cell contact in conjugates with sensitive MHC class I-negative targets but not in conjugates with resistant MHC class I-positive targets. Moreover, the negative signals between an NK cell and a target cell are transmitted by KIR at the site of membrane apposition, where inhibitory receptors become clustered with MHC class I ligands in a supramolecular structure known as an inhibitory NK immune synapse (IS). 9,10 KIR signaling is critical for blocking lipid raft polarization and NK cell cytotoxicity, both depending on movements of microtubuli and actin filaments. 11 The composition of adhesion, costimulatory, cytoskel-etal, and signaling molecules in the supramolecular activation clusters (SMACs) of the cytolytic and noncytolytic NK cell IS revealed profound differences. 12 Indeed, cytoskeleton remodel-ing and redistribution of NK cell signaling molecules occur mainly in cytolytic NK ...

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.