Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

Our research focuses on T cell-based immunotherapies, with a particular emphasis on addressing the intricate challenge of balancing immunotolerance with effective tumor immunity. One of our major goals is to deepen our understanding of the immune-related side effects associated with cancer immunotherapy. These include conditions such as graft-versus-host disease (GVHD), immune-related adverse events (irAEs), and immune effector cell-associated neurotoxicity syndrome (ICANS), all of which can significantly impact patient outcomes. Through exploration of microbiome interactions, immune signaling pathways, and novel target tissues, we aim to develop new strategies to prevent and manage these critical side effects of immunotherapy. Additionally, we are investigating how oncogenic signaling contributes to tumor immune escape in hematological malignancies, seeking to uncover novel mechanisms that may inform future therapeutic approaches.

Another major focus of our research is to enhance our understanding of the delicate balance between the graft-versus-leukemia (GVL) effect and GVHD. For this aim, we use different mouse models, in vitro immune cell culture and intestinal organoids as well as primary patient samples. Furthermore, we employ kinome profiling, scRNA-seq and scTCR-seq in order to refine our understanding of immune responses in both cancer and transplant immunology. This approach not only aims to improve treatment outcomes but also seeks to identify novel targets that can enhance the beneficial GVL effect without increasing the risk of GVHD. 

• SFB/TRR 167 NeuroMac
• Deutsche Krebshilfe
• 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

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)

• Schmidt D, Endres C, Hoefflin R, Andrieux G, Zwick M, Karantzelis N, Staehle HF, Vinnakota JM, Duquesne S, Mozaffari Jovein M, Pfeifer D, Becker H, Blazar BR, Zähringer A, Duyster J, Brummer T, Boerries M, Baumeister J, Shoumariyeh K, Li J, Green AR, Heidel FH, Tirosh I, Pahl HL, Leimkühler N, Köhler N, de Toledo MAS, Koschmieder S, Zeiser R. Oncogenic Calreticulin Induces Immune Escape by Stimulating TGFβ Expression and Regulatory T-cell Expansion in the Bone Marrow Microenvironment. Cancer Res. 2024 Sep 16;84(18):2985-3003. doi: 10.1158/0008-5472.CAN-23-3553. PMID: 38885318
• Maas-Bauer K, Köhler N, Stell AV, Zwick M, Acharya S, Rensing-Ehl A, König C, Kroll J, Baker J, Koßmann S, Pradier A, Wang S, Docquier M, Lewis DB, Negrin RS, Simonetta F. Single-cell transcriptomics reveal different maturation stages and sublineage commitment of human thymic invariant natural killer T cells. J Leukoc Biol. 2024 Jan 19;115(2):401-409. doi: 10.1093/jleuko/qiad113. PMID: 37742056
• Talvard-Balland N, Braun LM, Dixon KO, Zwick M, Engel H, Hartmann A, Duquesne S, Penter L, Andrieux G, Rindlisbacher L, Acerbis A, Ehmann J, Köllerer C, Ansuinelli M, Rettig A, Moschallski K, Apostolova P, Brummer T, Illert AL, Schramm MA, Cheng Y, Köttgen A, Duyster J, Menssen HD, Ritz J, Blazar BR, Boerries M, Schmitt-Gräff A, Sariipek N, Van Galen P, Buescher JM, Cabezas-Wallscheid N, Pahl HL, Pearce EL, Soiffer RJ, Wu CJ, Vago L, Becher B, Köhler N*, Wertheimer T*, Kuchroo VK*, Zeiser R*. Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice. J Clin Invest. 2024 Jun 25;134(16):e177460. doi: 10.1172/JCI177460. PMID: 38916965. (* shared last authors)
• 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.
• 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)
• 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.