Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity.
Natural killer (NK) cells play an important role in cancer immunosurveillance and may prevent tumor progression and metastasis due to their ability to mediate direct cellular cytotoxicity and by releasing immunoregulatory cytokines, which shape adaptive immune responses. Their reactivity is governed by various activating and inhibitory molecules expressed on target cells and reciprocal interactions with other hematopoietic cells such as dendritic cells. In mice, thrombocytopenia inhibits metastasis, and this is reversed by NK cell depletion, suggesting that platelets are an important additional player in NK cell-tumor interaction. Moreover, it has been shown that metastasizing tumor cells do not travel through the blood alone but are rapidly coated by platelets. However, the knowledge about the molecular mechanisms by which platelets influence NK cells is fragmentary at best. Here we show that platelet-derived soluble factors, secreted on coating of tumor cells or after stimulation with classic platelet agonists, impair NK cell antitumor reactivity resulting in diminished granule mobilization, cytotoxicity, and IFN-gamma production. The impaired NK cell reactivity was not due to induction of apoptosis but mediated by down-regulation of the activating immunoreceptor natural killer group 2, member D (NKG2D) on NK cells by platelet-derived transforming growth factor beta (TGF-beta). Neutralization of TGF-beta in platelet releasate not only prevented NKG2D down-regulation but also restored NK cell antitumor reactivity. Thus, our data elucidate the molecular basis of the previously described influence of platelets on NK cell antitumor reactivity and suggest that therapeutic intervention in tumor cell-platelet interaction and the resulting TGF-beta release by platelets may serve to enhance antitumor immunity.
Kopp
Hans-Georg
HG
Department of Hematology/Oncology, Eberhard Karls University, Tübingen, Germany.
Placke
Theresa
T
Salih
Helmut Rainer
HR
D001792:Blood Platelets / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000097:blood / Q000276:immunology*; D015539:Platelet Activation; D016212:Transforming Growth Factor beta / Q000097:blood / Q000276:immunology*
C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma