reported that the coating of myeloma cells with tumor-reactive antisyndecan-1 mAb promoted the cross-presentation of TA by DC to T cells. dendritic cells (DCs), and generation of TA-specific T lymphocyte responses. We present evidence supporting the induction of NK:DC cross talk, leading to priming of TA-specific cellular immunity. These observations show that mAb-mediated NK cell activation can be greatly enhanced by the action of stimulatory cytokines and surface molecules on maturing DC and that NK:DC interaction facilitates the recruitment of both NK cells and DC to the tumor site(s). The cooperative, reciprocal stimulatory activity of both NK cells and DC eIF4A3-IN-1 can modulate both the innate immune response in the local tumor microenvironment and the adaptive immune response in secondary lymphoid organs. These events likely contribute to clinical activity, as well as provide a potential biomarker of response to mAb therapy. receptor affinity, and the efficacy of antitumor mAb ADCC takes place upon interaction of Fc-region of mAb with immune cells, when the Fab region of the mAb binds to the antigenic epitope on tumor cells . This interaction induces the activation of FcELISPOT assay Open in a separate window Fig. 3 Cetuximab enhanced the cross-priming of EGFR-specific CTLs in the presence of NK cells. EGFR853C861 antigen-specific CTLs were stimulated with DC (from HLA-A2+ healthy donor) fed with EGFR-positive, HLA-A2? live PCI-15B HNC (Tu) either with cetuximab or isotype-matched control IgG1(each at 10 g/ml), with or without autologous NK cells (DC:NK: PCI-15B;1:1:1 ratio) for 48 h. Afterward, DC was incubated with na?ve CD8 T cells for 36 h, and the frequency of EGFR853C861 antigen-specific CTLs activated under indicated conditions were examined for IFN-production by ELISPOT TA-specific mAbs initiate NK:DC cross talk leading to cellular immunity Various reports indicate that antitumor mAb can generate T cell-based cellular immunity [1, 16]. Dhodhapkar et al. reported that the coating of myeloma cells with tumor-reactive antisyndecan-1 mAb promoted the cross-presentation of TA by DC to T cells. They also reported that the enhanced cross-presentation of TA was dependent on the Fcin NK cells. IFN-ELISPOT assays. DC incubated with PCI-15B HNC Rabbit Polyclonal to NUMA1 and cetuximab significantly enhanced (= 0.001) the eIF4A3-IN-1 cross-presentation of PCI-15B HNC cellular antigen to EGFR-specific CTL in the presence of NK cells. At basal level, the cross-presentation was observed alone by PCI-15B HNC without cetuximab, using a control IgG1 mAb or without NK cells (Fig. 3). Irrelevant specificity, control IgG1 isotype or IgG2 anti-EGFR mAb panitumumab failed to facilitate the enhancement of cross-presentation of these distinct TA in the presence or absence of NK cells. The findings presented above could reflect targeting of PCI-15B HNC to Fcsecretion can be greatly enhanced by the action of stimulatory cytokines (Fig. 2). NK:DC cross talk allows the recruitment of both NK cells and DC to the inflammatory sites [37, 41]. The eIF4A3-IN-1 cooperative activity of both NK cell and DC can modulate both the innate immune response in the local microenvironment and the adaptive immune response in secondary lymphoid organs. Specifically, NK cells in the presence of cytokines released by DC such as IL-12 become activated, regulating both the quality and the intensity of cellular immune responses. In turn, DC, in the presence of cytokines released by activated NK cells, such as IFN-secretion. However, distinct combinations of cytokines induced different cytokine profiles. The immunosuppresive cytokines, IL-10 and TGF- em eIF4A3-IN-1 /em , have a negative impact on the function of NK cells. This report described that the cytokine milieu at the inflammatory site may greatly affect the function of NK cells . Further studies specially examining the influence of mAb activation on these phenotypes and cell population are warranted. Conclusions The generation of TA-specific adaptive immune responses may offer substantial clinical benefit in response to treatment of cancer patients with therapeutic mAb. Indeed, mAb-based cancer therapy has very low side effects, similar to pharmacological inhibitors, but with the added benefit of TA-specific T cell priming and immunologic memory. In addition to their antiproliferative action against tumor cells, therapeutic mAb appears to trigger various immunological responses that may be responsible for their clinical activity. This cascade may be triggered by mAb-mediated ADCC, leading to the generation of a large amount of released TA, which can be engulfed, processed, and presented.