1. Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells
- Author
-
Li, Suwen, Wang, Chloe S, Montel-Hagen, Amélie, Chen, Ho-Chung, Lopez, Shawn, Zhou, Olivia, Dai, Kristy, Tsai, Steven, Satyadi, William, Botero, Carlos, Wong, Claudia, Casero, David, Crooks, Gay M, and Seet, Christopher S
- Subjects
Pluripotent Stem Cells ,Stem cell research [CP] ,T-Lymphocytes ,1.1 Normal biological development and functioning ,Adoptive ,Medical Physiology ,innate lymphoid cells ,Regenerative Medicine ,Vaccine Related ,Underpinning research ,Receptors ,Genetics ,Innate ,Lymphocytes ,Antigens ,Stem Cell Research - Embryonic - Human ,Cancer ,cancer immunotherapy ,CD19 ,chimeric antigen receptor ,Stem Cell Research - Induced Pluripotent Stem Cell ,Inflammatory and immune system ,T cell development ,Immunity ,Cell Differentiation ,adoptive cell therapy ,T-Cell ,Stem Cell Research ,Antigen ,Immunology [CP] ,Immunization ,Immunotherapy ,Biochemistry and Cell Biology ,pluripotent stem cells - Abstract
Generation of chimeric antigen receptor (CAR) Tcells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect Tcell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports invitro differentiation of PSCs to Tcells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of Tcell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. Tcells 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 Tcell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the Tcell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs.
- Published
- 2023