Journal
MOLECULAR CELL
Volume 83, Issue 4, Pages 622-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2022.12.029
Keywords
-
Categories
Ask authors/readers for more resources
By integrating single-cell chromatin accessibility and RNA-seq data, we identified the heterogeneous functional and dysfunctional states of CD8+ tumor-infiltrating lymphocytes and revealed common chromatin remodeling and key regulatory factors involved in this process.
Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring under-lying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with sin-gle-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our an-alyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcrip-tional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR ac-tivators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available