Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B.
OBJECTIVE
Cytotoxic lymphocytes interact with human tumor cells via the activating immunoreceptor NKG2D, recognizing a variety of stress-associated MIC and ULBP surface molecules. However, tumors can escape from this immunosurveillance by shedding NKG2D ligands (NKG2DL), rendering the soluble products detectable in patients' sera.


METHODS
To elucidate the clinical significance of NKG2DL diversity, we studied their expression on melanoma tissues and their presence as soluble molecules in sera from >200 melanoma patients and compared the latter with the well-established serum marker S100B.


RESULTS
Immunohistochemistry revealed a heterogeneous expression of MIC and ULBP2 molecules between and within melanoma metastases. Compared with MIC, ULBP2 was less frequently expressed. Accordingly, elevated levels of soluble ULBP2 (sULBP2) were detected in sera of melanoma patients less frequently than elevated levels of soluble MICA (sMICA), although both soluble NKG2DL (sNKG2DL) were significantly increased compared with sera of healthy controls (P < 0.0001). Strikingly, elevated concentrations of sULBP2, but not of sMICA, were strongly associated with disease progression (P < 0.0001) and tumor load (P = 0.0003). Elevated serum levels of either sNKG2DL correlated with reduced overall survival, albeit considerably stronger for sULBP2 (P < 0.0001) than for sMICA (P = 0.011). In early-stage (I-III) melanoma patients, only sULBP2 (P < 0.0001) but neither sMICA nor S100B revealed prognostic significance. Multivariate analysis identified sULBP2 (P = 0.0015) and S100B (P = 0.013) but not sMICA as independent predictors of prognosis.


CONCLUSIONS
Our data reveal marked differences in the clinical significance of individual sNKG2DL. Only sULBP2 is an independent predictor of prognosis, the significance of which is superior to the well-established and widely used melanoma serum marker S100B.
Paschen
Annette
A
Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center Heidelberg and University Medicine Mannheim, University Medicine Mannheim, Mannheim, Germany. a.paschen@dkfz.de
Sucker
Antje
A
Hill
Bettina
B
Moll
Iris
I
Zapatka
Marc
M
Nguyen
Xuan Duc
XD
Sim
Geok Choo
GC
Gutmann
Isabelle
I
Hassel
Jessica
J
Becker
Jürgen C
JC
Steinle
Alexander
A
Schadendorf
Dirk
D
Ugurel
Selma
S
D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009414:Nerve Growth Factors / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D011379:Prognosis; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D012878:Skin Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D012995:Solubility
D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C423230:ULBP2 protein, human