Abstract

Studies of haploidentical stem cell transplantation (SCT) demonstrate that NK cells play an important role in immunosurveillance of leukemia and indicate that acute lymphoblastic leukemias (ALL) are less susceptible to NK cell reactivity than acute myeloid leukemia (AML). The molecular mechanisms mediating NK cell reactivity against leukemia cells, especially those responsible for the differential susceptibility of AML and ALL to NK cell immunosurveillance, are yet largely unclear. Recently we have identified AICL as a myeloid-specific ligand for the activating NK cell receptor NKp80 (

Welte et al.,
Nat. Immunol.
2006
,
7
:
1334
). Here we studied the role of AICL and NKp80 in NK cell reactivity against acute leukemia. Substantial levels of AICL were expressed on blasts in 23 cases (40%) of 57 AML patients studied, while no AICL expression was detected on leukemic cells of 21 investigated ALL patients. Healthy CD34+ cells did also not express AICL, which suggests that AICL may be a marker for a malignant phenotype of myeloid hematopoietic precursor cells. Expression in AML was not restricted to a specific French-American-British (FAB) subtype, but was significantly associated with myelomonocytic differentiation (FAB M4 and M5). No correlation with a particular cytogenetic abnormality or expression levels of HLA class I was observed. Inhibition of AICL-NKp80 interaction by blocking NKp80 (Fab’)2 fragments significantly diminished both cellular cytotoxicity (>60% reduction, E:T ratio 40:1) and IFN-γ production (>60% reduction) of NK cells in cocultures with AICL-positive AML cells demonstrating that AICL expression renders AML blasts susceptible to NK cell reactivity. On NK cells of AML patients, expression of NKp80 was found to be significantly reduced compared to healthy donors. Cocultures of AICL- and control-transfectants with NK cells revealed that NKp80 expression is downregulated after interacting with its ligand, which provides a functional explanation how leukemia cells may evade NKp80-mediated NK cell immunosurveillance. Taken together, our data indicate that AICL-NKp80 interaction substantially contributes to NK cell reactivity against AML but not against ALL, which may explain the differential susceptibility of AML and ALL to NK cell reactivity. Our data further support the notion that NK cells play an important role in the pathophysiology of acute leukemia and provide useful information for therapeutic approaches in AML which, like e.g. haploidentical stem cell transplantation, rely on a sufficient NK cell response.

Disclosures: No relevant conflicts of interest to declare.

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