Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells

Suwen Li; Chloe S. Wang; Amélie Montel-Hagen; Ho-Chung Chen; Shawn Lopez; Olivia Zhou; Kristy Dai; Steven Tsai; William Satyadi; Carlos Botero; Claudia Wong; David Casero; Gay M. Crooks; Christopher S. Seet

Cell Reports (Mar 2023)

Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells

Suwen Li,
Chloe S. Wang,
Amélie Montel-Hagen,
Ho-Chung Chen,
Shawn Lopez,
Olivia Zhou,
Kristy Dai,
Steven Tsai,
William Satyadi,
Carlos Botero,
Claudia Wong,
David Casero,
Gay M. Crooks,
Christopher S. Seet

Affiliations

Suwen Li: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Chloe S. Wang: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
Amélie Montel-Hagen: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Ho-Chung Chen: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Shawn Lopez: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Olivia Zhou: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
Kristy Dai: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
Steven Tsai: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
William Satyadi: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
Carlos Botero: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
Claudia Wong: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA
David Casero: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Gay M. Crooks: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center (JCCC), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Christopher S. Seet: Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine (DGSOM), University of California, Los Angeles, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center (JCCC), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 3
p. 112241

Abstract

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Summary: Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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