CIBSS - Centre for integrative Biological Signalling StudiesCIBSS

Principal Investigators

Jun. Prof. Dr. Natalie Köhler

Junior Professor

Jun. Prof. Dr. Natalie Köhler

Kontakt

Jun. Prof. Dr. Natalie Köhler
Department of Internal Medicine I, Hematology and Oncology, University Medical Center, Faculty of Medicine)
Center for Translational Cell Research (ZTZ)

T +49 761 270 78171
natalie.koehler(at)uniklinik-freiburg.de

Weitere Informationen

Tumor immunology and T cell based immunotherapies

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.

10 selected publications:

  • Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans.
    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 (2020)
    Blood. 136(12):1442-1455.
  • MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors.
    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 (2020).
    JCI Insight. 5(6):e132334.
  • Intestinal Microbiota Influence Immune Tolerance post Allogeneic Hematopoietic Cell Transplantation and intestinal GVHD.
    Köhler N, Zeiser R (2019)
    Front Immunol. 9:3179.
  • MiR-146a controls immune response in the melanoma microenvironment.
    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 (2019)
    Cancer Res. 79(1):183-195.
  • MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT-signaling in dendritic cells after stem cell transplantation.
    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 (2017).
    Leukemia. 31(12):2732-2741.
  • Activation loop phosphorylation regulates B-Raf in vivo and transformation by B-Raf mutants.
    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 (2016)
    EMBO J. 35(2):143-61.
  • Complete Freund’s adjuvant induces experimental autoimmune myocarditis by enhancing IL-6 production during initiation of the immune response.
    Fontes JA, Barin JG, Talor MV, Stickel N (Köhler N), Schaub J, Rose NR, Ciháková D (2017)
    Immun Inflamm Dis. 5(2):163-176.
  • MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GvHD.
    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 (2014)
    Blood. 124(16):2586-95.
  • The Nlrp3 inflammasome regulates acute graft-versus-host disease
    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 (2013)
    J Exp Med. 210(10):1899-910. (* shared first authors)
  • The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia – CXCR4 antagonists as potential adjuvants for monoclonal antibodies.
    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 (2010)
    Br J Haematol. 151(2):167-78.