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CRISPR-based epigenome editing screens identify transcriptional and epigenetic regulators of human CD8 T cell function

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218988 | GEO | 2023/05/24

REPOSITORIES: GEO

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CRISPR-based epigenome editing screens identify transcriptional and epigenetic regulators of human CD8 T cell function [Sorting-based CRISPR screens]

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Project description:CRISPR-based epigenome editing screens identify transcriptional and epigenetic regulators of human CD8 T cell function [Sorting-based CRISPR screens]

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CRISPR-based epigenome editing screens identify transcriptional and epigenetic regulators of human CD8 T cell function

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Project description:Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.

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