Abstract
Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of the mTORC1/C2 inhibitor, AZD8055, in the manufacturing of clinically competent Treg cells and compare the effects with those induced by rapamycin (RAPA), another mTOR inhibitor commonly used in Treg expansion protocols.
Methods: Primary human Treg cells were isolated from leukapheresis product. Cell viability, expansion rates, suppressive function, autophagy, mitochondrial unfolded protein response (mitoUPR), and cell metabolic profile were assessed.
Results: We observed a stronger inhibition of the mTORC2 signaling pathway and downstream events triggered by Interleukin 2 (IL2)-receptor in AZD8055-treated cells compared with those treated with RAPA. AZD8055 induced progressive metabolic changes in mitochondrial respiration and glycolytic pathways that disrupted the long-term expansion and suppressive function of Tregs. Unlike RAPA, AZD8055 treatment impaired autophagy and enhanced the mitoUPR cell stress response pathway.
Conclusions: A distinct pattern of mTOR inhibition by AZD, compared with RAPA, induced mitochondrial stress response and dysfunction, impaired autophagy, and disrupted cellular bioenergetics, resulting in the loss of proliferative potential and suppressive function of Treg cells.
Document Type
Article
Publication Date
8-2023
Digital Object Identifier (DOI)
https://doi.org/10.3390/cells12162066
Funding Information
This research was funded in part by the AstraZeneca Open Innovation programme awarded to F.M. and R.G. This project was also supported by the University of Kentucky Alliance Research Initiative (TILT Alliance) to R.G., A.P.A., S.N.D., F.C., A.K. and F.M.
Repository Citation
Gedaly, Roberto; Orozco, Gabriel; Ancheta, Alexandre P.; Donoho, Mackenzie; Desai, Siddharth; Chapelin, Fanny; Khurana, Aman; Lewis, Lillie J.; Zhang, Cuiping; and Marti, Francesc, "Metabolic Disruption Induced by mTOR Signaling Pathway Inhibition in Regulatory T-Cell Expansion for Clinical Application" (2023). Markey Cancer Center Faculty Publications. 368.
https://uknowledge.uky.edu/markey_facpub/368
Notes/Citation Information
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).