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

Item Type:Article
Title:Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas
Creators Name:Kruschinski, A. and Moosmann, A. and Poschke, I. and Norell, H. and Chmielewski, M. and Seliger, B. and Kiessling, R. and Blankenstein, T. and Abken, H. and Charo, J.
Abstract: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.
Keywords:Immunotherapy, In Vivo Imaging, Tumor Biology, Tolerance, Retroviral Transduction, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:105
Number:45
Page Range:17481-17486
Date:11 November 2008
Official Publication:https://doi.org/10.1073/pnas.0804788105
PubMed:View item in PubMed

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