Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potential curative therapy option for patients with hematological malignancies and is based on the beneficial graft-versus-leukemia (GvL) effect, in which allogeneic T cells present in the graft recognize and eliminate residual leukemia cells. However, the allogeneic T cells can also attack healthy tissues of the recipient, resulting in graft-versus-host disease (GvHD), a severe and potentially life threatening complication of allo-HCT. Therefore, our lab is interested in further analysing the molecular mechanisms of these two effects, in order to find potential new therapies that target GvHD while sparing the beneficial GVL Effect. For this aim, we use classical genetic mouse models and T cell characterization approaches as well as novel NGS-based technologies, including single-cell RNA sequencing.

The second focus of our research is the identification of novel targets for immunotherapies in hematological malignancies, in particular key regulators of immune checkpoint molecules. With the development of immune checkpoint inhibitors (ICI), the treatment landscape of numerous cancer entities has been revolutionized. However, to date only a subset of patients responds to ICI therapy and ICI can also induce severe immune-related adverse events (irAEs), which oftentimes require ICI discontinuation and corticosteroid treatment, hence limiting the success of ICI therapy. Therefore, we are studying novel regulators of immune checkpoint molecules and how oncogenic signaling induces immune checkpoint molecule expression and immune escape in the context of hematological malignancies. Furthermore, we aim to elucidate the mechanisms of and find novel biomarkers for irAE development during ICI therapy.

• CIBSS Exzellenzcluster

• DFG SFB1160 IMPATH

• DFG SFB1479 OncoEscape

• ZPM

• Hans A. Krebs Medical Scientist Programme

• Else Kröner-Fresenius-Stiftung (EKFS)

• Mechtild Harf Research Grant (DKMS Foundation for Giving Life)

• Grünewald-Zuberbier-Stiftung Grant

Internal collaborations

• Melanie Börries (Insitut für Bioinformatik und System-Medizin)
• Robert Zeiser (Klinik für Innere Medizin I)
• Gerd Walz (Klinik für Innere Medizin IV)
• Susana Minguet (Institut für Biologie III)
• Peter Kohl (Universitäts-Herzzentrum Freiburg - Bad Krozingen)
• Tilman Brummer (Institut für Molekulare Medizin und Zellforschung)
• Olaf Groß (Institut für Neuropathologie)
• Tanja Hartmann (Klinik für Innere Medizin I)
• Kilian Eyerich (Klinik für Dermatologie und Venerologie)
• Marta Rizzi (Klinik für Rheumatologie und Klinische Immunologie)

External collaborations

• Dominic Grün (Universität Würzburg)
• Petya Apostolova (Universität Basel)
• Ami Bhatt (Stanford University, USA)
• Robert Negrin (Stanford University)
• Bruce Blazar (University of Minnesota, USA)
• Marcin Kortylewski (City of Hope National Medical Center)
• Juliane Walz (Universitätsklinikum Tübingen)
• Federico Simonetta (University of Geneva)

• Lohmeyer JK, Hirai T, Turkoz M, Buhler S, Lopes Ramos T, Köhler N, Baker J, Melotti A, Wagner I, Pradier A, Wang S, Ji X, Becattini S, Villard J, Merkler D, Chalandon Y, Negrin RS, Simonetta F.
  Analysis of the T-cell repertoire and transcriptome identifies mechanisms of regulatory T-cell suppression of GVHD.
  Blood. 2023 Apr 6;141(14):1755-1767. doi: 10.1182/blood.2022017982. PMID: 36574344.
• Rückert T, Andrieux G, Boerries M, Hanke-Müller K, Woessner NM, Doetsch S, Schell C, Aumann K, Kolter J, Schmitt-Graeff A, Schiff M, Braun LM, Haring E, Kissel S, Siranosian BA, Bhatt AS, Nordkild P, Wehkamp J, Jensen BAH, Minguet S, Duyster J, Zeiser R, Köhler N.
  Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling.
  Sci Transl Med. 2022 Dec 21;14(676):eabp9675. doi: 10.1126/scitranslmed.abp9675. Epub 2022 Dec 21. PMID: 36542690.
• Bauer J, Köhler N, Maringer Y, Bucher P, Bilich T, Zwick M, Dicks S, Nelde A, Dubbelaar M, Scheid J, Wacker M, Heitmann JS, Schroeder S, Rieth J, Denk M, Richter M, Klein R, Bonzheim I, Luibrand J, Holzer U, Ebinger M, Brecht IB, Bitzer M, Boerries M, Feucht J, Salih HR, Rammensee HG, Hailfinger S, Walz JS.
  The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.
  Nat Commun. 2022 Oct 27;13(1):6401. doi: 10.1038/s41467-022-33746-3. PMID: 36302754.
• Norona J, Apostolova P, Schmidt D, Ihlemann R, Reischmann N, Taylor G, Köhler N, de Heer J, Heeg S, Andrieux G, Siranosian BA, Schmitt-Graeff A, Pfeifer D, Catalano A, Frew IJ, Proietti M, Grimbacher B, Bulashevska A, Bhatt AS, Brummer T, Clauditz T, Zabelina T, Kroeger N, Blazar BR, Boerries M, Ayuk F, Zeiser R: Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood. 2020 Sep 17;136(12):1442-1455.
• Marschner D, Falk M, Hanke-Müller K, Javorniczky NR, Rawluk J, Duquesne S, Schmitt-Graeff A, Haring E, Aumann K, Marschner P, Dicks S, Rafei-Shamsabadi D, Meiss F, Boerries M, Duyster J, Zeiser R, Köhler N: MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors. JCI Insight. 2020 Mar 26;5(6):e132334.
• Köhler N, Zeiser R: Intestinal Microbiota Influence Immune Tolerance post Allogeneic Hematopoietic Cell Transplantation and intestinal GVHD. Front Immunol. 2019 Jan 17;9:3179. 
• Mastroianni J, Stickel N (Köhler N), Andrlová H, Hanke K, Melchinger W, Duquesne S, Schmidt D, Falk M, Andrieux G, Pfeifer D, Dierbach H, Schmitt-Graeff A, Meiss F, Boerries M, Zeiser R: MiR-146a controls immune response in the melanoma microenvironment. Cancer Res. 2019 Jan 1;79(1):183-195.
• Stickel N (Köhler N)*, Hanke K*, Marschner D, Prinz G, Köhler M, Melchinger W, Pfeifer D, Schmitt-Graeff A, Brummer T, Heine A, Brossart P, Wolf D, von Bubnoff N, Finke J, Duyster J, Ferrara J, Salzer U, Zeiser R: MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT-signaling in dendritic cells after stem cell transplantation. Leukemia. 2017 Dec;31(12):2732-2741. (* shared first authors)
• Fontes JA, Barin JG, Talor MV, Stickel N (Köhler N), Schaub J, Rose NR, Ciháková D: Complete Freund’s adjuvant induces experimental autoimmune myocarditis by enhancing IL-6 production during initiation of the immune response. Immun Inflamm Dis. 2017 Jun;5(2):163-176.
• Köhler M, Röring M, Schorch B, Heilmann K, Stickel N (Köhler N), Fiala GJ, Schmitt LC, Braun S, Ehrenfeld S, Uhl FM, Kaltenbacher T, Weinberg F, Herzog S, Zeiser R, Schamel WW, Jumaa H, Brummer T: Activation loop phosphorylation regulates B-Raf in vivo and transformation by B-Raf mutants. EMBO J. 2016 Jan 18;35(2):143-61.
• Stickel N (Köhler N), Prinz G, Pfeifer D, Hasselblatt P, Schmitt-Graeff A, Follo M, Thimme R, Finke J, Duyster J, Salzer U, Zeiser R: MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GvHD. Blood. 2014 Oct 16;124(16):2586-95.
• Stickel N (Köhler N), Zeiser R: The role of microRNAs in immunoregulation after allo-HCT. DMW. 2014 Aug;139(33):1673-8.
• Barin JG, Baldeviano GC, Talor MV, Wu L, Ong S, Fairweather D, Bedja D, Stickel N (Köhler N), Fontes JA, Cardamone AB, Zheng D, Gabrielson KL, Rose NR, Ciháková D (2013): Fatal eosinophilic myocarditis develops in the absence of IFN-γ and IL-17A. J Immunol. 2013 Oct 15;191(8):4038-47.
• Jankovic D*, Ganesan J*, Bscheider M*, Stickel N (Köhler N), Weber FC, Guarda G, Follo M, Pfeifer D, Tardivel A, Ludigs K, Bouazzaoui A, Kerl K, Fischer JC, Haas T, Schmitt-Gräff A, Manoharan A, Müller L, Finke J, Martin SF, Gorka O, Peschel C, Ruland J, Idzko M, Duyster J, Holler E, French LE, Poeck H, Contassot E, Zeiser R: The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med. 2013 Sep 23;210(10):1899-910. (* shared first authors)
• Buchner M, Brantner P, Stickel N (Köhler N), Prinz G, Burger M, Bär C, Dierks C, Pfeifer D, Ott A, Mertelsmann R, Gribben JG, Veelken H and Zirlik K: The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia – CXCR4 antagonists as potential adjuvants for monoclonal antibodies. Br J Haematol. 2010 Oct;151(2):167-78.