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.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/pharmacology , Immunologic Factors/pharmacology , Killer Cells, Natural/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Adult , Aged , Animals , Histocompatibility Antigens Class I/immunology , Humans , Killer Cells, Natural/drug effects , Male , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Natural Cytotoxicity Triggering Receptor 3/immunology , Neoplasm Transplantation , Rituximab , HLA-E AntigensABSTRACT
Human natural killer (NK) and gamma delta (gammadelta) T cells are potent effectors involved in the destruction of abnormal cells. Accumulating clinical and experimental data point towards a key role for NK cells and gammadelta T cells in the control of most, if not all, haematological malignancies. This review focuses on the alterations in these effector cells found in patients with haematological malignancies, which might explain an escape from innate immune surveillance. We discuss new anti-cancer drugs that target these effector cells indirectly or directly. Finally, we review future strategies that offer the possibility of enhancing the effector functions of NK and gammadelta T cells against haematological malignancies.
