AI Article Synopsis
- - Pluripotent stem cells (PSCs) are being explored as a source for off-the-shelf T cell immunotherapies, but their differentiation into mature T cells can lead to complications if not properly managed.
- - Researchers successfully generated mature T cells from genetically edited PSCs that lack specific T cell receptors (TCRs) and class I major histocompatibility complexes, using a combination of human and murine cells for T cell maturation.
- - The study found that these edited T cells demonstrated significantly improved tumor control in mouse models compared to those with intact TCRs, suggesting a promising approach for enhancing T cell immunotherapies derived from PSCs.
Article Abstract
Pluripotent stem cells (PSCs) are a promising source of allogeneic T cells for off-the-shelf immunotherapies. However, the process of differentiating genetically engineered PSCs to generate mature T cells requires that the same molecular elements that are crucial for the selection of these cells be removed to prevent alloreactivity. Here we show that antigen-restricted mature T cells can be generated in vitro from PSCs edited via CRISPR to lack endogenous T cell receptors (TCRs) and class I major histocompatibility complexes. Specifically, we used T cell precursors from RAG1RAG2B2M human PSCs expressing a single TCR, and a murine stromal cell line providing the cognate human major histocompatibility complex molecule and other critical signals for T cell maturation. Possibly owing to the absence of TCR mispairing, the generated T cells showed substantially better tumour control in mice than T cells with an intact endogenous TCR. Introducing the T cell selection components into the stromal microenvironment of the PSCs overcomes inherent biological challenges associated with the development of T cell immunotherapies from allogeneic PSCs.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11087257 | PMC |
| http://dx.doi.org/10.1038/s41551-023-01146-7 | DOI Listing |
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