Die DNA Damage induzierte Expression von Liganden für zytotoxische Rezeptoren auf NK Zellen: Die Rolle der DNA Damage Response für "Inside Out Signaling" in CLL
Zusammenfassung der Projektergebnisse
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.
Projektbezogene Publikationen (Auswahl)
- Natural ligands and antibody-based fusion proteins: harnessing the immune system against cancer. Trends Mol Med. 2014 Feb;20(2):72-82
Vyas M, Koehl U, Hallek M, Pogge von Strandmann E
(Siehe online unter https://doi.org/10.1016/j.molmed.2013.10.006) - Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology. 2015 Aug 12;5(4):e1071008
Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, Le Chevalier T, Livartoski A, Barlesi F, Laplanche A, Ploix S, Vimond N, Peguillet I, Théry C, Lacroix L, Zoernig I, Dhodapkar K, Dhodapkar M, Viaud S, Soria JC, Reiners KS, Pogge von Strandmann E, Vély F, Rusakiewicz S, Eggermont A, Pitt JM, Zitvogel L, Chaput N
(Siehe online unter https://doi.org/10.1080/2162402x.2015.1071008) - DNA damage response and evasion from immunosurveillance in CLL: new options for NK cell-based immunotherapies. Front Genet. 2015 Feb 4;6:11
Shatnyeva OM, Hansen HP, Reiners KS, Sauer M, Vyas M, Pogge von Strandmann E
(Siehe online unter https://doi.org/10.3389/fgene.2015.00011) - NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients. Oncoimmunology. 2016 Apr 25;6(1):e1137418
Rusakiewicz S, Perier A, Semeraro M, Pitt JM, Pogge von Strandmann E, Reiners KS, Aspeslagh S, Pipéroglou C, Vély F, Ivagnes A, Jegou S, Halama N, Chaigneau L, Validire P, Christidis C, Perniceni T, Landi B, Berger A, Isambert N, Domont J, Bonvalot S, Terrier P, Adam J, Coindre JM, Emile JF, Poirier-Colame V, Chaba K, Rocha B, Caignard A, Toubert A, Enot D, Koch J, Marabelle A, Lambert M, Caillat-Zucman S, Leyvraz S, Auclair C, Vivier E, Eggermont A, Borg C, Blay JY, Le Cesne A, Mir O, Zitvogel L
(Siehe online unter https://doi.org/10.1080/2162402x.2015.1137418) - CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells. Oncogene. 2017 Feb 16;36(7):933-941
Sauer M, Schuldner M, Hoffmann N, Cetintas A, Reiners KS, Shatnyeva O, Hallek M, Hansen HP, Gasser S, Pogge von Strandmann E
(Siehe online unter https://doi.org/10.1038/onc.2016.259)
