Chimeric antigen receptor–induced BCL11B suppression propagates NK-like cell development
Marcel Maluski, … , Marcel R.M. van den Brink, Martin G. Sauer
Marcel Maluski, … , Marcel R.M. van den Brink, Martin G. Sauer
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(12):5108-5122. https://doi.org/10.1172/JCI126350.
View: Text | PDF
Research Article Immunology

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.

Authors

Marcel Maluski, Arnab Ghosh, Jessica Herbst, Vanessa Scholl, Rolf Baumann, Jochen Huehn, Robert Geffers, Johann Meyer, Holger Maul, Britta Eiz-Vesper, Andreas Krueger, Axel Schambach, Marcel R.M. van den Brink, Martin G. Sauer

×

Figure 4

Transcriptional profile analysis locates CARiK cells at the interface of T lymphocytes and NK cells.

Options: View larger image (or click on image) Download as PowerPoint
Transcriptional profile analysis locates CARiK cells at the interface of...
(A) Schematic representation of the experimental setup for transcriptional comparison of CARiK cells and different lymphoid cell populations. Splenocytes of 12-week-old WT B6 mice were harvested and sorted for T cells (CD3+γδTCR–NK1.1–; n = 3), NKT cells (CD3+NK1.1+; n = 2), γδ T cells (CD3+γδTCR+; n = 2), and NK cells (CD3–NK1.1+; n = 4). Tom+ CARiK cells (n = 4) were harvested from recipients on day 28 and consecutively sorted. Extracted RNA samples from all lymphoid subsets were compared by microarray analysis. Experiment was performed once. (B) PCA analysis of transcriptional profiles derived from the sorted lymphoid cell populations. (C) Hierarchical clustering of the 500 most differentially expressed (adjusted P < 0.05) transcripts across CARiK cells and respective lymphoid lineages. (D) Selected transcripts expressed by lymphoid subsets were color coded according to function or lymphoid cell type. Orange: γδ T cells, NKT cells, and innate lymphocytes; purple: cytotoxicity mediators; red: inhibitory receptors; blue: T lymphocytes; green: NK cells.