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Elke Pogge von Strandmann / Bilal Alashkar Alhamwe: Deciphering the tumor-promoting activity of the NKG2D/NKG2D-ligand system in OC

AIM: NKG2D is an immunosurveillance receptor expressed on NK cells and subsets of invariant NKT and T cells. NKG2D-Ligand (NKG2D-L) expressing tumor cells are effectively eliminated by NKG2D⁺ effector cells at the early stages of tumorigenesis. At advanced stages, tumor cells lose their NKG2D-L expression on the cell surface and instead release them into the TME which inhibits NKG2D anti-tumor activity. The aim of this project is to decipher the complex roles of soluble, vesicle-associated, and cell-surface ligands in regulating NKG2D⁺ effector cell activity which may result in tumor restriction or promotion.

STATE of the ART: NKG2D (encoded by the killer cell lectin-like receptor subfamily K, member 1, or KLRK1 gene) is a C-type lectin receptor and a major activating immunoreceptor involved in tumor immune surveillance. Many studies validated the critical role of the NKG2D/NKG2D-L system for the control of tumor growth in cancer patients and tumor mouse models. Unexpectedly and paradoxically it was recently shown that the deficiency of NKG2D restricted tumor growth in a model of inflammation-driven liver cancer. Although the molecular mechanisms are unknown it is anticipated that NKG2D⁺ effector cells release inflammatory components (such as TNF-α, IFN-γ, and MIP1-α) and chemoattractants which indirectly lead to the accumulation of myeloid cells further secreting pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1α together shaping a tumor-promoting inflammatory TME.