Project 2

1. Applicant

2. Topic

Regulation of melanoma cell ligands binding to the activating immune receptor NKG2D

3. Short summary

The immune receptor NKG2D is known to function as an activating receptor on human Natural Killer (NK) cells, γδ T cells and as a co-stimulatory molecule on CD8+ αβ T lymphocytes. We demonstrated that signals sensed via NKG2D contribute to the killing of melanoma by autologous NK cells in vitro. Expression of the NKG2D ligands (NKG2DL) MICA and ULBP2 could be detected on melanoma cell lines and in melanoma tissues, although the in situ expression pattern within one tumor and between different tumors is quite heterogenous. So far, the regulation of NKG2DL expression in tumor cells is not sufficiently defined, despite of the fact that these molecules play an important role in the early immune defense of malignancies and that their therapeutic manipulation might support the generation of potent anti-tumor immune responses. The aim of the present project is to elucidate the mechanisms that regulate NKG2DL expression in melanoma by (I) determining the impact of aberrantly activated signaling pathways (RAS-RAF-MAPK, PI3K-AKT, STAT3 pathways) on NKG2DL expression, (II) identifying factors that control NKG2DL transcription, (III) analyzing the influence of the tumor microenvironment on NKG2DL expression.

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