Montel-Hagen Amélie, Crooks Gay M
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA; Broad Stem Cell Research Center, University of California, Los Angeles, CA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA.
Exp Hematol. 2019 Mar;71:24-31. doi: 10.1016/j.exphem.2018.12.001. Epub 2018 Dec 24.
The generation of T cells from human pluripotent stem cells (PSCs) opens a valuable experimental window into developmental hematopoiesis and raises the possibility of a new therapeutic approach for T-cell immunotherapy. After directing PSCs through mesoderm and early hematopoietic developmental stages, commitment to the T-cell lineage has been achieved by several groups using coculture with stromal cells that express a notch ligand, recapitulating the critical signals that initiate the first stages of normal T-cell differentiation in the thymus. However, positive selection and the production of mature T cells from human PSCs have been limited to date. Nonetheless, T-lineage cells have been generated from PSCs with tumor antigen specificity either through a prearranged clonal T-cell receptor (TCR) or lentiviral-mediated expression of chimeric antigen receptors. The recent development of a 3D artificial organoid model has demonstrated that PSCs can generate mature conventional T cells that are fully functional and express a diverse TCR repertoire. Introduction of a transgenic TCR at the PSC stage allows for the production of tumor-antigen-specific, mature conventional T cells. The tools of gene editing in PSCs are ideally suited to produce off-the-shelf universal products for T-cell immunotherapy. In this review, we describe the studies that have led to this exciting moment in PSC biology and discuss translation to clinical applications.
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