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

Nat Commun. 2024 Jan 10;15(1):446. doi: 10.1038/s41467-024-44703-7.

Kristina Maas-Bauer ^# ¹, Anna-Verena Stell ^# ¹, Kai-Li Yan ^# ¹, Enrique de Vega ^# ¹ ², Janaki Manoja Vinnakota ^# ¹, Susanne Unger ³, Nicolas Núñez ³, Johana Norona ¹, Nana Talvard-Balland ¹, Stefanie Koßmann ¹, Carsten Schwan ⁴, Cornelius Miething ¹, Uta S Martens ¹ ⁴, Khalid Shoumariyeh ¹ ⁵, Rosa P Nestor ¹, Sandra Duquesne ¹, Kathrin Hanke ¹, Michal Rackiewicz ⁶ ⁷, Zehan Hu ⁶ ⁷, Nadia El Khawanky ¹, Sanaz Taromi ¹, Hana Andrlova ¹, Hemin Faraidun ², Stefanie Walter ¹, Dietmar Pfeifer ¹, Marie Follo ¹, Johannes Waldschmidt ¹, Wolfgang Melchinger ¹, Michael Rassner ¹, Claudia Wehr ¹, Annette Schmitt-Graeff ⁸, Sebastian Halbach ⁵ ⁹, James Liao ¹⁰, Georg Häcker ¹¹, Tilman Brummer ⁵ ⁹ ¹², Joern Dengjel ⁶ ⁷, Geoffroy Andrieux ¹³, Robert Grosse ⁴ ¹⁴, Sonia Tugues ³, Bruce R Blazar ¹⁵, Burkhard Becher ³, Melanie Boerries ⁵ ¹³, Robert Zeiser ¹⁶ ¹⁷ ¹⁸

Affiliations

1 Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2 Faculty of Biology, University of Freiburg, Freiburg, Germany.
3 Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
4 Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Freiburg, Germany.
5 German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany.
6 Department of Biology, University of Fribourg, Fribourg, Switzerland.
7 Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
8 Institute of Pathology, University Hospital Freiburg, Freiburg, Germany.
9 IMMZ, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
10 Department of Medicine, University of Arizona, Tucson, USA.
11 IMMH, University Hospital Freiburg, Faculty of Medicine, Freiburg, Germany.
12 Signaling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
13 Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
14 CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
15 Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN, USA.
16 Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
17 German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
18 Signaling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
# Contributed equally.

PMID: 38199985 DOI: 10.1038/s41467-024-44703-7

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-50856

Ruxolitinib

99.99%, JAK1/2 Inhibitor

JAK; Autophagy; Mitophagy; Apoptosis

Cancer

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