Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses.
Ligands of the prototypical activating NK receptor NKG2D render cancer cells susceptible to NK cell-mediated cytolysis if expressed at sufficiently high levels. However, malignant cells employ mechanisms to evade NKG2D-mediated immunosurveillance, such as NKG2D ligand (NKG2DL) shedding resulting in reduced surface expression levels. In addition, systemic downregulation of NKG2D on NK cells of cancer patients has been observed in many studies and was attributed to soluble NKG2DL (sNKG2DL), although there also are conflicting data. Likewise, relevant expression of NKG2DL in leukemia has been reported by some, but not all studies. Hence, we comprehensively studied expression, release, and function of the NKG2D ligands MHC class I chain-related molecules A and B and UL16-binding proteins 1-3 in 205 leukemia patients. Leukemia cells of most patients (75%) expressed at least one NKG2DL at the surface, and all investigated patient sera contained elevated sNKG2DL levels. Besides correlating NKG2DL levels with clinical data and outcome, we demonstrate that sNKG2DL in patient sera reduce NKG2D expression on NK cells, resulting in impaired antileukemia reactivity, which also critically depends on number and levels of surface-expressed NKG2DL. Together, we provide comprehensive data on the relevance of NKG2D/NKG2DL expression, release, and function for NK reactivity in leukemia, which exemplifies the mechanisms underlying NKG2D-mediated tumor immunosurveillance and escape.
Department of Hematology and Oncology, Eberhard Karls University, D-72076 Tuebingen, Germany.
Julia
J
Hilpert
Ludger
L
Grosse-Hovest
Frank
F
Grünebach
Corina
C
Buechele
Tina
T
Nuebling
Tobias
T
Raum
Alexander
A
Steinle
Helmut Rainer
HR
Salih
D000328:Adult; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007938:Leukemia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015166:Monitoring, Immunologic / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C423230:ULBP2 protein, human