P02.09 Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating T cells. (21st September 2022)

• Record Type: Journal Article
• Authors: Schmidl, C; Riegel, D; Romero-Fernández, E; Simon, M; Adenugba, A; Singer, K; Mayr, R; Weber, F; Imbusch, CD; Kreutz, M; Brors, B; Ugele, I; Werner, JM; Siska, PJ
• Is Part Of: Journal for immunotherapy of cancer. Volume 10(2022)Supplement 1
• Page Start: A16
• Page End: A16
• Publication Date: 2022-09-21
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-ITOC9.28
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.