Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development Journal Article

   


Authors: Maluski, M.; Ghosh, A.; Herbst, J.; Scholl, V.; Baumann, R.; Huehn, J.; Geffers, R.; Meyer, J.; Maul, H.; Eiz-Vesper, B.; Krueger, A.; Schambach, A.; van den Brink, M. R. M.; Sauer, M. G.
Article Title: Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development
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. Copyright: © 2019, American Society for Clinical Investigation.
Keywords: controlled study; protein expression; nonhuman; cd3 antigen; cd8 antigen; t lymphocyte; mouse; cancer immunotherapy; transcription factor gata 3; gene expression; gene expression profiling; cell maturation; animal experiment; animal model; hematopoietic stem cell transplantation; in vivo study; cell differentiation; cytotoxicity; in vitro study; cell population; b cell lymphoma; gamma interferon; microarray analysis; progeny; transgene; chimeric antigen receptor; natural killer cell; adoptive transfer; cd4 antigen; ex vivo study; lymphoid progenitor cell; cell expansion; graft recipient; cd19 antigen; cd28 antigen; enzyme; notch3 receptor; antileukemic activity; degranulation; lymphoid cell; principal component analysis; cd56 antigen; priority journal; article; evaluation study; immunoreceptor tyrosine based activation motif; cd161 antigen; early antigen; real time reverse transcription polymerase chain reaction
Journal Title: Journal of Clinical Investigation
Volume: 129
Issue: 12
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2019-12-02
Start Page: 5108
End Page: 5122
Language: English
DOI: 10.1172/jci126350
PUBMED: 31479431
PROVIDER: scopus
PMCID: PMC6877334
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076005203&doi=10.1172%2fJCI126350&partnerID=40&md5=7d6f18b6aaec22545d7e844e7a608fa3
Notes: Source: Scopus
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MSK Authors
  1. Marcel R M Van Den Brink
    616 Van Den Brink
  2. Arnab Ghosh
    64 Ghosh
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