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.

Download full-text


Available from: R. Katherine Alpaugh
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells are a crucial part of the innate immune system and play critical roles in host anti-viral, anti-microbial, and antitumor responses. The elucidation of NK cell biology and their therapeutic use are actively being pursued with 200 clinical trials currently underway. In this review, we outline the role of NK cells in cancer immunotherapies and summarize current noninvasive imaging technologies used to track NK cells in vivo to investigate mechanisms of action, develop new therapies, and evaluate efficacy of adoptive transfer.
    Full-text · Article · Jun 2014 · Magnetic Resonance Insights
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The possibility to modulate ex vivo human NK cell differentiation towards specific phenotypes will contribute to a better understanding of NK cell differentiation and facilitate tailored production of NK cells for immunotherapy. In this study, we show that addition of a specific low dose of IL-12 to an ex vivo NK cell differentiation system from cord blood CD34(+) stem cells will result in significantly increased proportions of cells with expression of CD62L as well as KIRs and CD16 which are preferentially expressed on mature CD56(dim) peripheral blood NK cells. In addition, the cells displayed decreased expression of receptors such as CCR6 and CXCR3, which are typically expressed to a lower extent by CD56(dim) than CD56(bright) peripheral blood NK cells. The increased number of CD62L and KIR positive cells prevailed in a population of CD33(+)NKG2A(+) NK cells, supporting that maturation occurs via this subtype. Among a series of transcription factors tested we found Gata3 and TOX to be significantly downregulated, whereas ID3 was upregulated in the IL-12-modulated ex vivo NK cells, implicating these factors in the observed changes. Importantly, the cells differentiated in the presence of IL-12 showed enhanced cytokine production and cytolytic activity against MHC class I negative and positive targets. Moreover, in line with the enhanced CD16 expression, these cells exhibited improved antibody-dependent cellular cytotoxicity for B-cell leukemia target cells in the presence of the clinically applied antibody rituximab. Altogether, these data provide evidence that IL-12 directs human ex vivo NK cell differentiation towards more mature NK cells with improved properties for potential cancer therapies.
    Full-text · Article · Jan 2014 · PLoS ONE
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell transfer therapy for cancer has made a rapid progress recently and the immunotherapy has been recognized as the fourth anticancer modality after operation, chemotherapy, and radiotherapy. Lymphocytes used for cell transfer therapy include dendritic cells, natural killer (NK) cells, and T lymphocytes such as tumor-infiltrating lymphocytes (TILs) and cytotoxic T lymphocytes (CTLs). In vitro activated or engineered immune cells can traffic to cancer tissues to elicit persistent antitumor immune response which is very important especially after immunosuppressive treatments such as chemotherapy. In this review, we overviewed recent advances in the exploration of dendritic cells, NK cells, and T cells for the treatment of human cancer cells.
    Full-text · Article · Jan 2014 · Journal of Immunology Research
Show more