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

Kristina Maas-Bauer; Anna Verena Stell; Kai Li Yan; Enrique de 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; Robert Zeiser

doi:10.1038/s41467-024-44703-7

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

Kristina Maas-Bauer, Anna Verena Stell, Kai Li Yan, Enrique de 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 KhawankySanaz 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, Robert Zeiser

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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.

Original language	English (US)
Article number	446
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44703-7
State	Published - Dec 2024

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© 2024, The Author(s).

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Maas-Bauer, K., Stell, A. V., Yan, K. L., de Vega, E., Vinnakota, J. M., Unger, S., Núñez, N., Norona, J., Talvard-Balland, N., Koßmann, S., Schwan, C., Miething, C., Martens, U. S., Shoumariyeh, K., Nestor, R. P., Duquesne, S., Hanke, K., Rackiewicz, M., Hu, Z., ... Zeiser, R. (2024). ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease. Nature communications, 15(1), Article 446. https://doi.org/10.1038/s41467-024-44703-7

Maas-Bauer, K, Stell, AV, Yan, KL, de Vega, E, Vinnakota, JM, Unger, S, Núñez, N, Norona, J, Talvard-Balland, N, Koßmann, S, Schwan, C, Miething, C, Martens, US, Shoumariyeh, K, Nestor, RP, Duquesne, S, Hanke, K, Rackiewicz, M, Hu, Z, El Khawanky, N, Taromi, S, Andrlova, H, Faraidun, H, Walter, S, Pfeifer, D, Follo, M, Waldschmidt, J, Melchinger, W, Rassner, M, Wehr, C, Schmitt-Graeff, A, Halbach, S, Liao, J, Häcker, G, Brummer, T, Dengjel, J, Andrieux, G, Grosse, R, Tugues, S, Blazar, BR, Becher, B, Boerries, M & Zeiser, R 2024, 'ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease', Nature communications, vol. 15, no. 1, 446. https://doi.org/10.1038/s41467-024-44703-7

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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.",

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AU - de Vega, Enrique

AU - Vinnakota, Janaki Manoja

AU - Unger, Susanne

AU - Núñez, Nicolas

AU - Norona, Johana

AU - Talvard-Balland, Nana

AU - Koßmann, Stefanie

AU - Schwan, Carsten

AU - Miething, Cornelius

AU - Martens, Uta S.

AU - Shoumariyeh, Khalid

AU - Nestor, Rosa P.

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AU - Hanke, Kathrin

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AU - Hu, Zehan

AU - El Khawanky, Nadia

AU - Taromi, Sanaz

AU - Andrlova, Hana

AU - Faraidun, Hemin

AU - Walter, Stefanie

AU - Pfeifer, Dietmar

AU - Follo, Marie

AU - Waldschmidt, Johannes

AU - Melchinger, Wolfgang

AU - Rassner, Michael

AU - Wehr, Claudia

AU - Schmitt-Graeff, Annette

AU - Halbach, Sebastian

AU - Liao, James

AU - Häcker, Georg

AU - Brummer, Tilman

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AU - Andrieux, Geoffroy

AU - Grosse, Robert

AU - Tugues, Sonia

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

Abstract

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