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The DNA damage-dependent expression of ligands for cytotoxic NK-cell receptors: Impact of the DNA damage response on inside out signaling in CLL

Subject Area Hematology, Oncology
Term from 2013 to 2017
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 226262100
 

Final Report Abstract

Chronic lymphocytic leukemia of B cells (B-CLL) represents the most common form of leukemia in the western world with very heterogeneous clinical prognosis. It is characterized by progressive outgrowth of monoclonal, mature and apoptosis-resistant B cells in peripheral blood, bone marrow as well as lymph nodes and spleen. A defect immune system is a hallmark of CLL and associated with severe infections and lack of anti-tumor immune responses. Within this project we showed that a dysregulated expression of ligands for the activating NK cell receptors NKG2D and NKp30 (in response to DNA damage) was associated with a diminished NK cell anti-tumor activity in CLL and other malignant diseases. We identified the acetyltransferases CBP and p300 as crucial regulators for both, the proper expression of NKG2D-ligands on the surface of CLL cells and for the release of extracellular vesicles harboring the NKp30-ligand BAG6. We provide evidence that the effects of vesicles released by tumor cells are not restricted to NK cell functions but generally influence the tumor microenvironment via transport of proteins and RNAs. In a follow up project, we aim to uncover the role of CLL-released extracellular vesicles for non-malignant cells within the tumor surrounding. Based on our previous work we hypothesize that extracellular vesicles modulate the fate of healthy bystander cells, which in turn support cancer cell growth and survival, collectively leading to their activation and evasion from the host immune system. Towards translation of the findings we decorated CLL target cells with a recombinant NKG2D-ligand fused to the tumor antigen CD19 to rescue anti-tumor immunity. This protein sensitized CLL cells to NK cell-dependent killing and revealed anti-tumor activity in a CLL xenograft model . Next, targeting of innate lymphocytes (NK cells) against CLL cells will be combined with immune check point inhibitors targeting T cells. This approach will be pre-clinically evaluated using defined genetic models for CLL.

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