Background Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood.
Materials and Methods We use single-cell chromatin profiling and integrate publicly available single-cell RNA-seq data of TILs from several patients over four cancer entities to study gene-regulation in T cell (dys-)function.
Results We identify gene-regulatory landscapes in a wide breadth of CD8+ TIL functional states. Our analysis predicts enhancer-promoter interactions in human TILs and prioritizes key elements by super-enhancer analysis. We define a human common chromatin trajectory to T cell dysfunction and determine involved key enhancers, transcriptional regulators, and deregulated target genes in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors.
Conclusions Our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
Disclosure Information C. Schmidl: None. D. Riegel: None. E. Romero-Fernández: None. M. Simon: None. A. Adenugba: None. K. Singer: None. R. Mayr: None. F. Weber: None. C.D. Imbusch: None. M. Kreutz: None. B. Brors: None. I. Ugele: None. J.M. Werner: None. P.J. Siska: None.
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