Blocking NK Cell Inhibitory Self-Recognition Promotes Antibody-Dependent Cellular Cytotoxicity in a Model of Anti-Lymphoma Therapy

Department of Medical Oncology and Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2008; 180(9):6392-401. DOI: 10.4049/jimmunol.180.9.6392
Source: PubMed


Human NK cells lyse Ab-coated target cells through the process of Ab-dependent cellular cytotoxicity (ADCC). Improving ADCC responses is desirable because it is thought to be an important antitumor mechanism for some Abs. NK cell inhibitory receptors, such as killer cell Ig-like receptors, engage with MHC class I molecules on self-cells to block NK cell activation. Accordingly, we enhanced ADCC responses by blocking NK cell inhibitory receptors, thus perturbing induction of the self-recognition signal. In a cell line model of anti-lymphoma therapy, the combination of rituximab with an Ab that blocks inhibitory self-recognition yielded increased NK cell-mediated target cell lysis when compared with rituximab alone. To validate this proof-of-concept, we then used a more representative approach in which an individual's fresh primary NK cells encountered autologous, EBV-transformed B cells. In this system, rituximab and a combination of Abs that block NK cell inhibitory receptors yielded improved NK cell-mediated lysis over rituximab alone. The results show, for the first time, that disruption of inhibitory self-recognition can efficiently promote ADCC in a human model, applying an autologous system in which physiologic checkpoints are in place. This method provides an alternative approach to potentiate the therapeutic benefit of antitumor Abs that mediate ADCC.

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    • "To take advantage of the alloreactivity of NK cells, they are expanded and activated in vitro prior to adoptive transfer using various cytokines (IL-2, IL-15, or IL-21) and growth factors.21,22 NK cell function can also be enhanced by blocking inhibitory KIR with monoclonal antibodies.23 "
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    • "The enhanced expression of CD16 generated under the influence of IL-12 might therefore be utilized in therapeutic settings combining the cytotoxic activity of ex vivo NK cells with antibodies against malignant cells. Previous studies revealed the potential and importance of the clinically approved antibody rituximab recognizing CD20 on B-cell leukemias in combination with human peripheral blood NK cells [18], [47]. In this regard we could confirm increased ADCC activity of the IL-12 modulated ex vivo NK cells against two B-cell lines coated with rituximab (Figure 6D). "
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    • "Therefore, NK cell-mediated cell lysis can be enhanced by using antibodies blocking NK inhibitory receptors or antibodies targeting activating receptors. For example, antibody blocking KIR significantly promoted NK cell Ab-dependent cellular cytotoxicity (ADCC) responses in a human cancer model [26]. Another experiment demonstrated using RNA interference that there was observed silencing NKG2A and increased NK cell lysis by 40% [27]. "
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