ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease

Kristina Maas-Bauer, Anna-Verena Stell, Kai-Li Yan, Enrique Vega, Janaki Manoja Vinnakota, Susanne Unger, Nicolas Núñez, Johana Norona, Nana Talvard-Balland, Stefanie Koßmann, Carsten Schwan, Cornelius Miething, Uta S. Martens, Khalid Shoumariyeh, Rosa P. Nestor, Sandra Duquesne, Kathrin Hanke, Michal Rackiewicz, Zehan Hu, Nadia El Khawanky, Sanaz Taromi, Hana Andrlova, Hemin Faraidun, Stefanie Walter, Dietmar Pfeifer, Marie Follo, Johannes Waldschmidt, Wolfgang Melchinger, Michael Rassner, Claudia Wehr, Annette Schmitt-Graeff, Sebastian Halbach, James Liao, Georg Häcker, Tilman Brummer, Joern Dengjel, Geoffroy Andrieux, Robert Grosse, Sonia Tugues, Bruce R. Blazar, Burkhard Becher, Melanie Boerries and Robert Zeiser ()
Additional contact information
Kristina Maas-Bauer: University of Freiburg
Anna-Verena Stell: University of Freiburg
Kai-Li Yan: University of Freiburg
Enrique Vega: University of Freiburg
Janaki Manoja Vinnakota: University of Freiburg
Susanne Unger: University of Zurich
Nicolas Núñez: University of Zurich
Johana Norona: University of Freiburg
Nana Talvard-Balland: University of Freiburg
Stefanie Koßmann: University of Freiburg
Carsten Schwan: University of Freiburg
Cornelius Miething: University of Freiburg
Uta S. Martens: University of Freiburg
Khalid Shoumariyeh: University of Freiburg
Rosa P. Nestor: University of Freiburg
Sandra Duquesne: University of Freiburg
Kathrin Hanke: University of Freiburg
Michal Rackiewicz: University of Fribourg
Zehan Hu: University of Fribourg
Nadia El Khawanky: University of Freiburg
Sanaz Taromi: University of Freiburg
Hana Andrlova: University of Freiburg
Hemin Faraidun: University of Freiburg
Stefanie Walter: University of Freiburg
Dietmar Pfeifer: University of Freiburg
Marie Follo: University of Freiburg
Johannes Waldschmidt: University of Freiburg
Wolfgang Melchinger: University of Freiburg
Michael Rassner: University of Freiburg
Claudia Wehr: University of Freiburg
Annette Schmitt-Graeff: University Hospital Freiburg
Sebastian Halbach: German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg
James Liao: University of Arizona
Georg Häcker: IMMH, University Hospital Freiburg, Faculty of Medicine
Tilman Brummer: German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg
Joern Dengjel: University of Fribourg
Geoffroy Andrieux: University of Freiburg
Robert Grosse: University of Freiburg
Sonia Tugues: University of Zurich
Bruce R. Blazar: University of Minnesota
Burkhard Becher: University of Zurich
Melanie Boerries: German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg
Robert Zeiser: University of Freiburg

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Patients with corticosteroid-refractory acute graft-versus-host disease (aGVHD) have a low one-year survival rate. Identification and validation of novel targetable kinases in patients who experience corticosteroid-refractory-aGVHD may help improve outcomes. Kinase-specific proteomics of leukocytes from patients with corticosteroid-refractory-GVHD identified rho kinase type 1 (ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histological GVHD severity in mice and was synergistic with JAK1/2 inhibition, without compromising graft-versus-leukemia-effects. ROCK1/2-inhibition in macrophages or dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with CD80, CD86, MHC-II expression and IL-6, IL-1β, iNOS and TNF production in myeloid cells. This was accompanied by impaired T cell activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and DC migration. NF-κB signaling was reduced in myeloid cells following ROCK1/2 inhibition. In conclusion, ROCK1/2 inhibition interferes with immune activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings.

Date: 2024
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DOI: 10.1038/s41467-024-44703-7

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