Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

Abstract

The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI-103, and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation.

SOX11 regulates apoptosis and cell cycle in hepatocellular carcinoma via Wnt/β‐catenin signaling pathway

“…In our study, SOX11‐induced NLK expression promoted the phosphorylation of TCF4 and thus blunted Wnt/β‐catenin cascade . On the other hand, aberrant activation of Wnt/β‐catenin signaling pathway is also reported to contribute to the development of chemoresistance in cancers, including HCC , which may explain our observation that SOX11 sensitized HuH‐7 to cisplatin and 5‐fluorouracil treatment. Taken together, the present study establishes a SOX11/NLK/Wnt/β‐catenin axis in suppressing the malignant behaviors of HCC cells.…”

In vitro evaluation of anti-hepatoma activity of brevilin A: involvement of Stat3/Snail and Wnt/β-catenin pathways

“…21 It has been denoted that Wnt/b-catenin signaling plays a critical role in liver development, liver regeneration, and liver zonation. 22,23 Furthermore, aberrant activation of this signaling pathway has been found in HCC, and has been correlated with tumor progression and poor prognosis. 22 Thus, Wnt/b-catenin pathway is considered as a potential application for the treatment of HCC.…”

“…22,23 Furthermore, aberrant activation of this signaling pathway has been found in HCC, and has been correlated with tumor progression and poor prognosis. 22 Thus, Wnt/b-catenin pathway is considered as a potential application for the treatment of HCC. 22 We found that brevilin A reduced the expressions of b-catenin and c-Myc, which are two important members in the Wnt/b-catenin pathway.…”

“…22 Thus, Wnt/b-catenin pathway is considered as a potential application for the treatment of HCC. 22 We found that brevilin A reduced the expressions of b-catenin and c-Myc, which are two important members in the Wnt/b-catenin pathway. The results suggested that brevilin A blocked the activation of the Wnt/bcatenin pathway in HCC cells.…”

mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation

“…The production of large numbers of clinical grade cells entails the ex vivo expansion of Tregs in GMPcompatible conditions. Addition of RAPA is of standard use in these protocols since the targeting of the mTOR pathway leads to a preferential or selective expansion of Tregs over conventional T cells (Tconv) [20][21][22][23] and the stability of FoxP3 expression after in vivo transfer. 24 In a recent study, we reported that the dual targeting of PI3K and mTOR is also inducing the preferential expansion of mouse and human Tregs, and the resulting cells are able to promote in vivo tolerance.…”