Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D.
The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.
Krockenberger
Mathias
M
Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.
Dombrowski
Yvonne
Y
Weidler
Claudia
C
Ossadnik
Monika
M
Hönig
Arnd
A
Häusler
Sebastian
S
Voigt
Heike
H
Becker
Jürgen C
JC
Leng
Lin
L
Steinle
Alexander
A
Weller
Michael
M
Bucala
Richard
R
Dietl
Johannes
J
Wischhusen
Jörg
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001201:Ascites; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape
C527085:KLRK1 protein, human; D008263:Macrophage Migration-Inhibitory Factors; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D016212:Transforming Growth Factor beta