DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy
K Töpfer, M Cartellieri, S Michen… - The Journal of …, 2015 - journals.aai.org
K Töpfer, M Cartellieri, S Michen, R Wiedemuth, N Müller, D Lindemann, M Bachmann…
The Journal of Immunology, 2015•journals.aai.orgNK cells are emerging as new effectors for immunotherapy of cancer. In particular, the
genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to
redirect NK cells to otherwise NK cell–resistant tumor cells. On the basis of DNAX-activation
protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of
activating NK cell receptors, we generated a new type of CAR targeting the prostate stem
cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti–PSCA-DAP12 …
genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to
redirect NK cells to otherwise NK cell–resistant tumor cells. On the basis of DNAX-activation
protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of
activating NK cell receptors, we generated a new type of CAR targeting the prostate stem
cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti–PSCA-DAP12 …
Abstract
NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell–resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti–PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv (AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti–PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy.
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