The Epigenetic Immuno-oncology Laboratory is interested in the molecular mechanisms of gene regulation in the context of cancer immunity. We are particularly focused on the non-coding genome, which we explore using high-throughput (single-cell) sequencing approaches to study immune cells and their interacting friends and foes. We work closely together with clinical collaboration partners to address the topics of cancer and inflammation with the vision to translate our findings for the patient’s well-being. Below you can find more details on our current projects.

Visualization of scATAC-seq Human CD8+ TILs using Uniform Manifold Approximation and Projection (UMAP)

Gene-regulatory pathways driving T cell (dys-)function in cancer

CD8+ T cells can detect and destroy malignant cells. Nevertheless, they often fail to do so. This is partly due to the fact that T cells can be rendered dysfunctional in the tumor. On the cellular level, chronic antigen exposure and the suppressive microenvironment drive this process of dysfunction, which is accompanied by the remodeling of the T cells’ chromatin landscapes. We use state-of-the-art single-cell sequencing approaches to dissect the heterogeneous chromatin and transcriptional patterns of human tumor-infiltrating T cells. This gives us a deeper insight into the underlying molecular processes that shape T-cell function and dysfunction. We then explore the possibilities of deleting T-cell dysfunction-driver genes in T cells and chimeric antigen receptor (CAR) T cells in order to improve their function in immunotherapeutic settings. Within the SFB221, we investigate how innate immune-sensing pathways can be harnessed to improve donor lymphocyte-directed graft-versus-leukemia effects in allogeneic stem cell transplantations.

Manipulation of enhancers and promoters in immune cells

Although many studies map chromatin/epigenome changes in T cells, there is a lack of understanding as to how individual enhancers contribute to T-cell phenotypes and function. We use artificial CRISPR activators and repressors to target non-coding gene-regulatory elements.

Our goal is to understand the role of individual gene-regulatory elements in controlling the cell-state-specific gene expression of critical immune genes. As enhancers bind cell-state and signal-specific transcription factors, we probe the possibilities of fine-tuning gene expression and interfering with detrimental signaling cues from the cancer microenvironment.

Dynamic gene regulation of metastasis

Cancer metastasis is responsible for ~90% of cancer-related deaths. It is a complex process comprising several stages in which the tumor progresses to invade and colonize distant sites. Cellular mechanisms central to this include the activation of Epithelial-Mesenchymal Transition (EMT), local invasion, intravasation, resilience against the bloodstream, extravasation, and establishment of tumor cells in the tissues of the organ where metastasis will form.

Moreover, these stages are no longer viewed as a linear cascade of events, but they represent multiple parallel, overlapping routes, which are accompanied by substantial reprogramming of the cancer cell’s gene-regulatory landscape. In close collaboration with Doctor Simone Brabletz from the Friedrich Alexander University of Erlangen-Nürnberg, we investigate the role of non-coding gene-regulatory elements in pancreatic cancer and metastatic progression. We focus on EMT-transcription factors and study how they are involved in driving gene-expression patterns that are essential for metastasis formation.

Visit the complete list of our Research Group’s publications on PubMed:

https://scholar.google.de/citations?user=qFeznaMAAAAJ&hl=de

Here is a selection of the most important publications from the last few years:

Riegel D*, Romero-Fernandez E*, Simon M*, Adenugba AR, Singer K, Mayr R, Weber F, Kleemann M, Imbusch CD, Kreutz M, Brors B, Ugele I, Werner JM, Siska PJ, Schmidl C. Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8(+) T cells. Mol Cell. 2023 Feb 16. 83:622-636 e610. doi:10.1016/j.molcel.2022.12.029. PMID: 36657444

Babl N, Decking SM, Voll F, Althammer M, Sala-Hojman A, Ferretti R, Korf C, Schmidl C, Schmidleithner L, Nerb B, Matos C, Koehl GE, Siska P, Bruss C, Kellermeier F, Dettmer K, Oefner PJ, Wichland M, Ugele I, Bohr C, Herr W, Ramaswamy S, Heinrich T, Herhaus C, Kreutz M et al. MCT4 blockade increases the efficacy of immune checkpoint blockade. J Immunother Cancer. 2023 Oct. 11doi:10.1136/jitc-2023-007349. PMID: 37880183

Rendeiro AF, Krausgruber T, Fortelny N, Zhao F, Penz T, Farlik M, Schuster LC, Nemc A, Tasnady S, Reti M, Matrai Z, Alpar D^#, Bodor C^#, Schmidl C^#, Bock C^#. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL. Nat Commun. 2020 Jan 29. 11:577. doi:10.1038/s41467-019-14081-6. PMID: 31996669

Feldker N, Ferrazzi F, Schuhwerk H, Widholz SA, Guenther K, Frisch I, Jakob K, Kleemann J, Riegel D, Bonisch U, Lukassen S, Eccles RL, Schmidl C, Stemmler MP, Brabletz T, Brabletz S. Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer. EMBO J. 2020 Sep 1. 39:e103209. doi:10.15252/embj.2019103209. PMID: 32692442

Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C^#, Feuerer M^#. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity. 2020 Feb 18. 52:295-312 e211. doi:10.1016/j.immuni.2019.12.002. PMID: 31924477

Schmidl C*, Vladimer GI*, Rendeiro AF*, Schnabl S*, Krausgruber T, Taubert C, Krall N, Pemovska T, Araghi M, Snijder B, Hubmann R, Ringler A, Runggatscher K, Demirtas D, de la Fuente OL, Hilgarth M, Skrabs C, Porpaczy E, Gruber M, Hoermann G, Kubicek S, Staber PB, Shehata M, Superti-Furga G, Jager U et al. Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL. Nat Chem Biol. 2019 Mar. 15:232-240. doi:10.1038/s41589-018-0205-2. PMID: 30692684

Datlinger P, Rendeiro AF, Schmidl C, Krausgruber T, Traxler P, Klughammer J, Schuster LC, Kuchler A, Alpar D, Bock C. Pooled CRISPR screening with single-cell transcriptome readout. Nat Methods. 2017 Mar. 14:297-301. doi:10.1038/nmeth.4177. PMID: 28099430

Rendeiro AF*, Schmidl C*, Strefford JC*, Walewska R, Davis Z, Farlik M, Oscier D, Bock C. Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks. Nat Commun. 2016 Jun 27. 7:11938. doi:10.1038/ncomms11938. PMID: 27346425

Schmidl C*, Rendeiro AF*, Sheffield NC, Bock C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat Methods. 2015 Oct. 12:963-965. doi:10.1038/nmeth.3542. PMID: 26280331

Schmidl C, Renner K, Peter K, Eder R, Lassmann T, Balwierz PJ, Itoh M, Nagao-Sato S, Kawaji H, Carninci P, Suzuki H, Hayashizaki Y, Andreesen R, Hume DA, Hoffmann P, Forrest AR, Kreutz MP, Edinger M, Rehli M, and the FANTOM consortium. Transcription and enhancer profiling in human monocyte subsets. Blood. 2014 Apr 24. 123:e90-99. doi:10.1182/blood-2013-02-484188. PMID: 24671955

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jorgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014 Mar 27. 507:455-461. doi:10.1038/nature12787. PMID: 24670763

Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res. 2009 Jul. 19:1165-1174. doi:10.1101/gr.091470.109. PMID: 19494038

Many thanks to the funding agencies who support our work:

2023–2025: German Cancer Aid (DKH)
Enhancement of CAR T cell function with CRISPR activation and interference.

2022–2025: SFB TRR 221
Timed targeting of cGAS/STING to improve tissue regeneration and antitumor responses following allo-HSCT

2021–2024: SFB TRR 305
EMT-dependent transcriptional enhancers important for metastatic colonization

2017–2022: German Reserach Foundation (DFG)
Tumor microenvironment-directed epigenome remodeling of tumor-infiltrating T cells

2020: 10x Genomics
High-throughput dissection of gene-regulatory element manipulations in T cells using single-cell RNA sequencing

Dr. Christian Schmidl

Head of Research Group | Epigenetic Immuno-oncology

Tel: +49 941 944–18176
Email: christian.schmidl@ukr.de

Research team

Dr. Christian Schmidl

Head of Research Group | Epigenetic Immuno-oncology

Dr. Gayatri Kavishwar

Postdoctoral Scientist

Manuela Kovács-Sautter

Research Technician

Elena Romero-Fernández

PhD Student

Chiara Suriano

PhD Student

Marianna Maddaloni

PhD Student

Julia von Poblotzki

PhD Student

Janek Spiekers

Master Student

Lab Life

There is life outside the laboratory: The Leibniz Institute places great value on our scientists developing the team spirit both in and out of work. Here are the photos to prove it!