Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas

NK cells are promising effectors for tumor adoptive immunotherapy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-11, Vol.105 (45), p.17481-17486
Main Authors: Kruschinski, Anna, Moosmann, Andreas, Poschke, Isabel, Norell, Håkan, Chmielewski, Markus, Seliger, Barbara, Kiessling, Rolf, Blankenstein, Thomas, Abken, Hinrich, Charo, Jehad
Format: Article
Language:English
Subjects:
Animals
Antigens
Biological Sciences
Carcinoma
Carcinoma - immunology
Carcinoma - therapy
Cell lines
Cells
Cytokines
DNA-Binding Proteins - genetics
Gene expression
Genetic Engineering - methods
Genetic Vectors - genetics
Humans
Immunotherapy, Adoptive - methods
K562 cells
Killer Cells, Natural - immunology
Luciferases
Mice
Mice, Knockout
Natural killer cells
Natural killer T cells
Receptor, ErbB-2 - immunology
Receptor, ErbB-2 - metabolism
Receptors
Rodents
T lymphocytes
Tumor cell line
Tumors
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Summary:NK cells are promising effectors for tumor adoptive immunotherapy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these cells lose MHC class I surface expression. Therefore, we targeted primary human NK cells by gene transfer of an activating chimeric receptor specific for HER-2, which is frequently overexpressed on carcinomas. We found that these targeted NK cells were specifically activated upon recognition of all evaluated HER-2 positive tumor cells, including autologous targets, as indicated by high levels of cytokine secretion as well as degranulation. The magnitude of this specific response correlated with the level of HER-2 expression on the tumor cells. Finally, these receptor transduced NK cells, but not their mock transduced counterpart, efficiently eradicated tumor cells in RAG2 knockout mice as visualized by in vivo imaging. Taken together, these results indicate that the expression of this activating receptor overrides inhibitory signals in primary human NK cells and directs them specifically toward HER-2 expressing tumor cells both in vitro and in vivo.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0804788105