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

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Corticosteroid-refractory acute graft-versus-host disease (aGVHD) is associated with poor patient survival.
• Identifying novel therapeutic targets is crucial for improving outcomes in refractory aGVHD.

Purpose of the Study:

• To identify and validate novel targetable kinases in patients with corticosteroid-refractory aGVHD.
• To evaluate the therapeutic potential of targeting rho kinase type 1 (ROCK1) in aGVHD.

Main Methods:

• Kinase-specific proteomics of leukocytes from aGVHD patients identified ROCK1 as upregulated.
• ROCK1/2 inhibition was tested in mouse models of aGVHD, alone and in combination with JAK1/2 inhibitors.
• Mechanistic studies investigated the effects of ROCK1/2 inhibition on myeloid cell function and T cell activation.

Main Results:

• ROCK1/2 inhibition significantly improved survival and reduced GVHD severity in mice.
• ROCK1/2 inhibition showed synergy with JAK1/2 inhibition without compromising graft-versus-leukemia (GVL) effects.
• Inhibition of ROCK1/2 in myeloid cells reduced pro-inflammatory cytokine production, impaired T cell activation, and inhibited cell migration.

Conclusions:

• ROCK1/2 inhibition effectively reduces acute GVHD severity through multiple mechanisms, including modulation of immune cell activation and migration.
• ROCK1/2 inhibition represents a promising therapeutic strategy for corticosteroid-refractory aGVHD, maintaining GVL effects.
• Targeting ROCK1/2 offers a potential new avenue for improving outcomes in patients with refractory aGVHD.