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P02.09 Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating T cells
  1. C Schmidl1,
  2. D Riegel1,
  3. E Romero-Fernández1,
  4. M Simon2,
  5. A Adenugba3,
  6. K Singer4,
  7. R Mayr5,
  8. F Weber6,
  9. CD Imbusch7,
  10. M Kreutz4,
  11. B Brors7,
  12. I Ugele8,
  13. JM Werner3 and
  14. PJ Siska4
  1. 1Leibniz Institute for Immunotherapy, Regensburg, Germany
  2. 2Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
  3. 3Department of Surgery, University Hospital Regensburg, Regensburg, Germany
  4. 4Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
  5. 5Department of Urology, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany
  6. 6Institute of Pathology, University of Regensburg, Regensburg, Germany
  7. 7Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  8. 8Department of Otorhinolaryngology, University Hospital Regensburg, Regensburg, Germany


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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