Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.

Patients with pulmonary graft-versus-host disease (pGVHD) have poor prognosis following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Further, pGVHD pathogenesis is not fully elucidated in humans, and currently available immunosuppressants are inadequately effective. We performed pathological evaluation of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation. Patient pathology was characterized by bronchiolitis and subpleural perivascular inflammation, with B cell, monocyte, and T cell accumulation around bronchioles. Bronchiolitis, perivascular inflammation, and peribronchial macrophage aggregation were also identified in a murine pGVHD model following transplant of bone marrow cells and splenocytes from C57BL/6 to B10.BR mice. Among MEK inhibitors, cobimetinib, but not trametinib, improved survival rates. Cobimetinib attenuated bronchiolitis, improved airway resistance and lung compliance in the mice, and suppressed activation of B cells and TNF-α production by monocytes in vitro, whereas these features were not suppressed by trametinib or tacrolimus. Further, cobimetinib suppressed activation of PI3K/AKT signaling, resulting in B cell and monocyte suppression. Dual inhibition of the MEK/ERK and PI3K/AKT pathways using a combination of trametinib and the PI3K inhibitor, taselisib, strongly suppressed B cell activation in vitro and improved mouse survival rate compared with vehicle or monotherapy with trametinib or taselisib. Imaging mass cytometry of human pGVHD revealed that T cells around bronchioles were positive for phosphorylated ERK, while B cells were positive for phosphorylated AKT. Thus, perivascular inflammation and bronchiolitis mediated by activation of the MEK/ERK and PI3K/AKT pathways are essential for pGVHD and represent a potential novel therapeutic target in humans.