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. 2012 Jun;32(3):632-46.
doi: 10.1007/s10875-011-9624-5. Epub 2012 Feb 9.

Primary B-CLL Resistance to NK Cell Cytotoxicity Can Be Overcome in Vitro and in Vivo by Priming NK Cells and Monoclonal Antibody Therapy

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Primary B-CLL Resistance to NK Cell Cytotoxicity Can Be Overcome in Vitro and in Vivo by Priming NK Cells and Monoclonal Antibody Therapy

Caroline Veuillen et al. J Clin Immunol. .

Abstract

Despite recent advances with monoclonal antibody therapy, chronic lymphocytic leukemia (CLL) remains incurable. Natural killer (NK) cells are potent antitumoral effectors, particularly against hematological malignancies. Defective recognition of B-CLL leukemic cells by NK cells has been previously described. Here, we deciphered the mechanisms that hamper NK cell-mediated clearance of B-CLL and evaluated the potential of NK cells as therapeutic tools for treatment of CLL. First of all, leukemic B cells resemble to normal B cells with a weak expression of ligands for NK receptors. Conversely, NK cells from B-CLL patients were functionally and phenotypically competent, despite a decrease of expression of the activating receptor NKp30. Consequently, resting allogeneic NK cells were unable to kill leukemic B cells in vitro. These data suggest that patients' NK cells cannot initiate a proper immune reaction due to a lack of leukemic cell recognition. We next set up a xenotransplantation mouse model to study NK-CLL cell interactions. Together with our in vitro studies, in vivo data revealed that activation of NK cells is required in order to control B-CLL and that activated NK cells synergize to enhance rituximab effect on tumor load. This study points out the requirements for immune system manipulation for treatment of B-CLL in combination with monoclonal antibody therapy.

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