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.
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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

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Figure 5

CAR expression early during lymphoid progenitor cell differentiation is required for CARiK cell generation at the expense of T cell development.

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CAR expression early during lymphoid progenitor cell differentiation is ...
(A–D) Irradiated B6 recipients received 3 × 106 B6 TCD-BM and either 8 × 106 im1928z1-generated lymphoid progenitors or iTom-generated lymphoid progenitors. CAR expression was either induced early (day 0) or late (day 21) after HSCT. Indicated time points refer to the day after transplantation. (B) Frequencies of CD3+TCRβ+ cells were analyzed within the transgene-positive gate on day 35 in both the BM and spleens. (C) Comparative analysis of NK1.1+ cells in spleens of early versus late im1928z1-generated lymphoid progenitor recipients on day 35 after AT. (B and C) Each analysis was done with n = 4 mice. Gating was done on the Tom+ population. Statistics were performed using 1-way ANOVA with Tukey’s post test. Data represent mean ± SEM. ***P < 0.001. (D) CD19+ B cell recovery (left) and frequencies of Tom+ cells (right) in the PB of transplant recipients after early or late im1928z1 induction (n = 3–4 mice per group and time point). Results from 1 of 2 independent experiments are shown.