Nowbakht, Pegah. Tumor recognition by natural killer cells in acute myeloid leukemia and after hematopoietic stem cell transplantation. 2005, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_7210
Natural killer (NK) cell-mediated cytolytic activity against tumors requires the
engagement of activating NK cell receptors by the tumor-associated ligands. Here, we
studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition
of human leukemia.
Hematopoietic stem cell transplantation (HSCT) is a common therapy in acute myeloid
leukemia (AML) and newly developing NK cells are important for engraftment and
antitumor immunity and thus for treatment outcome. Here, we studied the recovery and
functional activity of NK cells after allogeneic HSCT.
Analysis of ULBP1, ULBP2 and ULBP3, the recently identified ligands for NKG2D, and
of the yet not defined ligands for NKp30, NKp44 and NKp46 in healthy hematopoietic
cells demonstrated ligand expression by peripheral blood (PB) derived B cells,
monocytes, granulocytes and platelets. We show that upregulation of cell surface ligands
occurs during myeloid development with ligand-negative bone marrow (BM)-derived
CD34+ progenitor cells acquiring ligand expression upon myeloid maturation in vivo and
in vitro. ULBP1 and putative ligands for NKp30, NKp44 and NKp46 were further
elevated by stimulation with interferon (IFN)-γ.
In acute myeloid leukemia (AML), leukemic blasts from about 80% of patients expressed
very low levels of NKG2D- and NCR-specific ligands. Treatment with differentiationpromoting
myeloid growth factors, flt3 ligand (FL), stem cell factor (SCF) and
granulocyte macrophage colony-stimulating factor (GM-CSF) together with IFN-γ
upregulated cell surface levels of ULBP1 and putative NCR ligands on AML blasts,
conferring an increased sensitivity to NK cell-mediated lysis.
We conclude that the ligand-negative/low phenotype in AML is a consequence of cell
maturation arrest upon malignant transformation and that defective expression of ligands
for the activating NKG2D and NCR receptors may be an underlying cause for
compromised leukemia recognition by NK cells. In addition, NK cells were significantly
decreased in AML patients, but they expressed NKG2D and the NCRs at normal high
levels, providing a further argument for a dominant role of activating ligands and not
their respective receptors in immune escape in AML.
Analysis of NK cells after allogeneic HSCT revealed a rapid reconstitution of NK cells,
which reached normal levels as soon as 1 month after HSCT. However, there was a
skewing of NK cell subpopulations, with a prevalence of IFN-γ producing
CD56brightCD16dim/- NK cells and a corresponding reduction in the highly cytotoxic
CD56dimCD16bright subset. Expression of the triggering receptor NKp46 in NK cells from
transplanted patients was high. Our results indicate that fast recovering NK cells may
have important implications in the prevention of leukemic relapses after allogeneic
Altogether these data indicate that low expression of ligands for activating NK cell
receptors on leukemic blasts results in poor immunogenicity of tumor cells. Moreover, in
vivo upregulation of those ligands on target cells by appropriate compounds might
improve recognition of blasts by NK cells, including the early developing allogeneic NK
cells after HSCT, and thus reduce leukemic relapses.
|Committee Members:||Erb, Peter and Wodnar-Filipowicz, Aleksandra|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||111|
|Last Modified:||13 Mar 2009 11:20|
|Deposited On:||13 Feb 2009 16:12|
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