Novel feeder cells for the expansion of NKG2C+ natural killer cells from the blood of HCMV-seropositive donors
Despite intensive research, the cure of patients with glioblastoma multiforme (GBM), an aggressive brain tumor, is not possible. A promising approach to treat GBM is the adoptive cell transfer of tumor reactive NK cells.
The project focuses on NKG2C+ NK cells, a terminal differentiated subset of natural killer cells (NK cells). With their activating NKG2C receptor, these cells recognize HLA-E molecules presenting activating peptides derived from signal peptides of some classical HLA allelic variants and non-classical HLA-G, which can be found in increased amounts on the surface of glioblastoma cells. However, the proportion of NKG2C+ NK cells in peripheral blood is very low. Exceptions to this are humane cytomegalovirus (HCMV)-seropositive donors which contain increased frequencies of NKG2C+ NK cells. Yet, the cell numbers are far too low for future NKG2C-based immunotherapies. We are therefore developing methods to selectively expand functional NKG2C+ NK cell subsets from the blood of HCMV-seropositive donors ex vivo by using feeder cells. The feeder cells not only produce the interleukins and co-stimulatory ligands required for the growth of the NK cells, but also express artificial HLA-E-derivatives containing appropriate activating peptides required for activation of NK cells through the NKG2C receptor. The phenotype of expanded NKG2C+ NK cells is analyzed in detail and their cytotoxicity when encountering KIR:KIR-ligand matched as well as KIR:KIR-ligand mismatched GBM cells is investigated to elucidate a potential role of NKG2C+ NK cells in tumor immunosurveillance.