Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy.
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.
Laboratoire Immunologie et Cancer, INSERM U 1068, Centre de Recherche en Cancérologie de Marseille, 27 Bd Leï Roure, BP 30059, 13273, Marseille, France.
Caroline
C
Veuillen
Thérèse
T
Aurran-Schleinitz
Rémy
R
Castellano
Jérôme
J
Rey
Françoise
F
Mallet
Florence
F
Orlanducci
Laurent
L
Pouyet
Sylvaine
S
Just-Landi
Diane
D
Coso
Vadim
V
Ivanov
Xavier
X
Carcopino
Réda
R
Bouabdallah
Yves
Y
Collette
Cyril
C
Fauriat
Daniel
D
Olive
D000328:Adult; D000368:Aged; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000276:immunology; D009368:Neoplasm Transplantation; D000069283:Rituximab; D000097625:HLA-E Antigens
D058846:Antibodies, Monoclonal, Murine-Derived; D015395:Histocompatibility Antigens Class I; D007155:Immunologic Factors; D055628:Natural Cytotoxicity Triggering Receptor 3; D000069283:Rituximab; D000097625:HLA-E Antigens; C431710:NCR3 protein, human