Mechanisms of resistance to natural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia.
OBJECTIVE
Natural killer (NK) cell-mediated cytotoxicity contributes to the innate immune response against numerous malignancies, including leukemias. Acute lymphoblastic leukemias (ALL) often display a high degree of resistance, the mechanisms of which have not been elucidated.


METHODS
We used the well-characterized NK cell line NK-92 as a model to investigate whether mechanisms commonly implicated in tumor escape from NK cell killing are relevant for ALL.


RESULTS
We demonstrate selective resistance of B-precursor ALL to NK-92 cytotoxicity even in the absence of inhibitory killer cell immunoglobulin-like receptors (KIR), except for KIR2DL4. We also show that human leukocyte antigen-G, a ligand of KIR2DL4, expressed on a subset of ALL, does not mediate resistance of NK-cell mediated lysis. Similarly, intracellular adhesion molecule/lymphocyte function-associated antigen-1 interaction did not contribute significantly to resistance. In contrast the NK-sensitive T-ALL (MOLT-4) expressed moderate amounts of MHC class I chain-related gene AB (MICA/B) a ligand for the NK cell activating receptor NKG2D, while expression of MICA/B was absent in resistant B-ALL cell lines.


CONCLUSIONS
The NK cell-resistance of B-lineage ALLs does not appear to involve inhibitory mechanisms, but suggests deficient NK cell activation. Thus, immunostrategies designed to enhance ALL sensitivity toward NK cell-mediated cytotoxicity should focus on mechanisms of NK cell activation.
Romanski
Annette
A
Center for Internal Medicine, Department of Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany.
Bug
Gesine
G
Becker
Sven
S
Kampfmann
Manuela
M
Seifried
Erhard
E
Hoelzer
Dieter
D
Ottmann
Oliver G
OG
Tonn
Torsten
T
D001402:B-Lymphocytes; D002051:Burkitt Lymphoma / Q000276:immunology*; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000276:immunology; D054340:Receptors, KIR; D054345:Receptors, KIR2DL4; D055607:Receptors, Natural Killer Cell; D019139:Tumor Escape
D015395:Histocompatibility Antigens Class I; C515079:KIR2DL4 protein, human; C527085:KLRK1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054345:Receptors, KIR2DL4; D055607:Receptors, Natural Killer Cell