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Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development.
Maluski, Marcel Ghosh, Arnab Herbst, Jessica Scholl, Vanessa Baumann, Rolf Huehn, Jochen Geffers, Robert Meyer, Johann Maul, Holger Eiz-Vesper, Britta
Maluski, Marcel
Ghosh, Arnab
Herbst, Jessica
Scholl, Vanessa
Baumann, Rolf
Huehn, Jochen
Geffers, Robert
Meyer, Johann
Maul, Holger
Eiz-Vesper, Britta
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2019-12-02
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Abstract
The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during early phases of ex vivo generation of lymphoid progenitors suppressed BCL11B, leading to suppression of T cell-associated gene expression and acquisition of NK cell-like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients, CAR-expressing lymphoid progenitors differentiated into CAR-induced killer (CARiK) cells that mediated potent antigen-directed antileukemic activity even across MHC barriers. CD28 and active immunoreceptor tyrosine-based activation motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene expression and encourage further evaluation of ex vivo-generated CARiK cells for targeted immunotherapy.
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J Clin Invest. 2019 Dec 2;129(12):5108-5122. doi: 10.1172/JCI126350.
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Article
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en
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1558-8238
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Attribution-NonCommercial-ShareAlike 4.0 International