Mechanisms of resistance to natural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia

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. 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. 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. 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.