Area A - Biology and Molecular Oncology

Prof. Dr. Annette Paschen

Department of Dermatology

University Hospital Essen

Phone: +49 201 723 2406
Email

IFNγ -induced cell state transition in melanoma

The cytokine IFNγ is released by T lymphocytes in the course of an anti-tumor immune response. IFNγ-driven JAK1/2-STAT1 signalling in tumor cells can induce cell death, which is critical for T cell-mediated disease control. Also, the clinical success of melanoma immunotherapy is dependent on intact JAK1/2-STAT1 signalling in tumor cells. In line with this, resistance to immunotherapy has been associated with defective IFNγ signaling in melanoma cells caused by inactivating JAK1/2 mutations. But, therapy resistance, which is a major challenge in clinical care, cannot be explained solely by genetic alterations in tumor cells. Recently, melanoma cell plasticity emerged as a barrier to effective therapy. The capacity to switch between different transcriptional programs and transit between heterogeneous cell states allows melanoma cells to adapt to and survive selective pressures of the microenvironment. We observed that some melanoma cells escape IFNγ-induced cell death by switching into a non-proliferative IFNγ-tolerant cell state. Those cells resume proliferation upon cytokine depletion, thereby contributing to disease progression. Within the CRC1430 we aim to identify central regulators of IFNγ-induced cell state transition, monitor state transition at the single cell level and define phenotypic cell state heterogeneity. Understanding the development, maintenance and specific features of IFNγ-tolerant melanoma cells will uncover new therapeutic targets allowing us to shift the balance from IFNγ-tolerance towards cell death in order to improve the efficacy of melanoma immunotherapy.

Project Members

Dr. Fang Zhao

fang.zhao@uk-essen.de

Dr. Johanna A. Seier

johannaandrea.seier@uk-essen.de

Publications

    Journal articles

  • Stupia, Simone; Heeke, Christina; Brüggemann, Alicia; Zaremba-Montenari, Anne; Thier, Beatrice; Kretz, Julia; Sucker, Antje; Philip, Manuel; Zelinskyy, Gennadiy; Ferrone, Soldano; Rösch, Alexander; Horn, Susanne; Hadaschik, Eva; Schadendorf, Dirk; Trilling, Mirko; Dittmer, Ulf; Griewank, Klaus; Zhao, Fang; Paschen, Annette
    HLA class II loss and JAK1/2 deficiency coevolve in melanoma leading to CD4 T cell and IFNγ cross-resistance
    In: Clinical Cancer Research Vol. 29 (2023) Nr. 15, pp. 2894 - 2907
  • Váraljai, Renáta; Zimmer, Lisa; Al-Matary, Yahya; Kaptein, Paulien; Albrecht, Lea J.; Shannan, Batool; Brase, Jan C.; Gusenleitner, Daniel; Amaral, Teresa; Wyss, Nina; Utikal, Jochen; Flatz, Lukas; Rambow, Florian; Reinhardt, Hans Christian; Dick, Jenny; Engel, Daniel; Horn, Susanne; Ugurel, Selma; Sondermann, Wiebke; Livingstone, Elisabeth; Sucker, Antje; Paschen, Annette; Zhao, Fang; Placke, Jan-Malte; Klose, Jasmin M.; Fendler, Wolfgang; Thommen, Daniela S.; Helfrich, Iris; Schadendorf, Dirk; Rösch, Alexander
    Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma
    In: Nature Cancer Vol. 4 (2023) Nr. 9, pp. 1292 - 1308
  • Thier, Beatrice; Zhao, Fang; Stupia, Simone; Brüggemann, Alicia; Koch, Johannes; Schulze, Nina; Horn, Susanne; Coch, Christoph; Hartmann, Gunther; Sucker, Antje; Schadendorf, Dirk; Paschen, Annette
    Innate immune receptor signaling induces transient melanoma dedifferentiation while preserving immunogenicity
    In: Journal for ImmunoTherapy of Cancer Vol. 10 (2022) Nr. 6, e003863
  • Chauvistré, Heike; Shannan, Batool; Daignault-Mill, Sheena M.; Ju, Robert J.; Picard, Daniel; Egetemaier, Stefanie; Váraljai, Renáta; Gibhardt, Christine S.; Sechi, Antonio; Kaschani, Farnusch; Keminer, Oliver; Stehbens, Samantha J.; Liu, Qin; Yin, Xiangfan; Jeyakumar, Kirujan; Vogel, Felix C. E.; Krepler, Clemens; Rebecca, Vito W.; Kubat, Linda; Lueong, Smiths S.; Forster, Jan; Horn, Susanne; Remke, Marc; Ehrmann, Michael; Paschen, Annette; Becker, Jürgen; Helfrich, Iris; Rauh, Daniel; Kaiser, Markus; Gul, Sheraz; Herlyn, Meenhard; Bogeski, Ivan; Rodríguez-López, José Neptuno; Haass, Nikolas K.; Schadendorf, Dirk; Rösch, Alexander
    Persister state-directed transitioning and vulnerability in melanoma
    In: Nature Communications Vol. 13 (2022) Nr. 1, 3055