Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs

Abstract

Acute graft-versus-host disease is still a major cause of transplant-related mortality after allogeneic stem cell transplantation. It requires immunosuppressive treatments that broadly abrogate T cell responses, including beneficial ones directed against tumor cells or infective pathogens. Inhibition of the heat shock protein of 90 kDa has been demonstrated to eliminate tumor cells, as well as alloreactive T cells while preserving antiviral T cell immunity. Here, we show that the suppressive effects of heat shock protein of 90 kDa inhibition on alloreactive T cells were synergistically enhanced by concomitant inhibition of the PI3K/Akt signaling pathway, which is also strongly activated upon allogeneic stimulation. Molecular analyses revealed that this antiproliferative effect was mainly mediated by induction of cell-cycle arrest and apoptosis. In addition, we observed an increased proportion of activated regulatory T cells, which critically contribute to acute graft-versus-host disease control, upon combined heat shock protein of 90 kDa/Akt isoforms 1 and 2 or heat shock protein of 90 kDa/PI3K/p110δ isoform inhibition. Moreover, antiviral T cell immunity was functionally preserved after combined heat shock protein of 90 kDa/Akt isoforms 1 and 2 inhibition. Taken together, our data suggest that the combined heat shock protein of 90 kDa/PI3K/Akt inhibition approach represents a reasonable dual strategy to suppress residual tumor growth and efficiently deplete alloreactive T cells and thus, provide a rationale to prevent and treat acute graft-versus-host disease selectively without impairing pathogen-specific T cell immunity.

Improvement of Sclerodermatous Graft-Versus-Host Disease in Mice by Niclosamide

“…Indeed, this drug inhibits the phosphorylation of ERK 1/2 and AKT and blocks the Notch signaling pathway in different cell lines (Huang et al, 2016;Liang et al, 2015;Wieland et al, 2013). All of these pathways are involved in the physiopathology of GVHD (Allen et al, 2012;Berges et al, 2015;Lu et al, 2008;Zhang et al, 2011). In our hands, we observed an abrogation of the activation of these three pathways along with the improvement of the disease.…”

Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

“…1 T cells, 45,58 allowing preservation of antiviral immunity. Recent studies have suggested that Hsp90 inhibition using 17-AAG-protected intestine paneth cells against alloreactive T-cell-mediated injury, leading to improved epithelium regeneration and reduction of damage to the gastrointestinal track.…”

Obese donor mice splenocytes aggravated the pathogenesis of acute graft-versus-host disease via regulating differentiation of Tregs and CD4+ T cell induced-type I inflammation

“…As is known, the Akt/mTOR pathways have been reported to play prominent roles in T cell proliferation, T cell activation, migration, cytokine production and pathogenicity in the induction of aGVHD [ 31 , 32 ]. S1PR1 has been shown to be important in inflammatory responses in immune cells, the decreased expression of S1PR1 can attenuate aGVHD in mouse model [ 33 , 34 ].…”

“…Firstly, active Akt/mTOR signaling suppresses the function of Tregs and significantly impairs expression of Foxp3 [ 69 , 70 ]. Inhibiting AKT can attenuate aGVHD and increase Tregs [ 31 ]. Our and other group also found that active Akt signaling can aggravate the pathogenesis of aGVHD and reduce the proportion of Tregs [ 6 , 71 ].…”