ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
Kristina Maas‐Bauer, A. Stell, Kaili Yan, Enrique de Vega, Janaki Manoja Vinnakota, Susanne Unger, Nicolás Gonzalo Núñez, Johana Norona, Nana Talvard-Balland, S Kossmann, Carsten Schwan, Cornelius Miething, Uta Sabine Sabine Martens, Khalid Shoumariyeh, R Nestor, Sandra Duquesne, Kathrin Hanke, Michal Rackiewicz, Zehan Hu, Nadia El Khawanky, Sanaz Taromi, Hana Andrlová, Hemin Faraidun, Stefanie Walter, Dietmar Pfeifer, Marie Follo, Johannes M. Waldschmidt, Wolfgang Melchinger, Michael Rassner, Claudia Wehr, Annette Schmitt‐Graeff, Sebastian Halbach, James K. Liao, Georg Häcker, Tilman Brummer, Jörn Dengjel, Geoffroy Andrieux, Robert Grosse, Sònia Tugues, Bruce R. Blazar, Burkhard Becher, Melanie Boerries, Robert Zeiser
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.