Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells

• DOI: 10.1016/j.molcel.2022.12.029
• Publication Date: 2023-01-18T17:15:31Z
• Authors: Dania Riegel; Elena Romero-Fern...; Malte Simon; Akinbami Raphael ...; Katrin Singer; Roman Mayr; Florian Weber; Mark Kleemann; Charles D. Imbusch; Marina Kreutz; Benedikt Brors; Ines Ugele; Jens M. Werner; Peter J. Siska; Christian Schmidl
• Keywords: Enhancer RNAs; Epigenomics; ChIA-PET

Despite extensive studies on the chromatin landscape of exhausted T cells, transcriptional wiring underlying heterogeneous functional and dysfunctional states human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth CD8+ TIL covering four cancer entities using single-cell profiling. We map enhancer-promoter interactions TILs by integrating accessibility with RNA-seq data from tumor-entity-matching samples prioritize cell-state-specific genes super-enhancer analysis. Besides revealing entity-specific remodeling TILs, our analyses common trajectory to dysfunction determine key enhancers, regulators, deregulated involved this process. Finally, validate enhancer regulation at immunotherapeutically relevant loci targeting non-coding regulatory elements potent CRISPR activators repressors. In summary, study provides framework for understanding manipulating cues lymphocytes.