Combinatorial genetic engineering strategy for immune protection of stem cell-derived beta cells by chimeric antigen receptor regulatory T cells.

Autor:	Barra JM; Diabetes Institute, University of Florida, Gainesville, FL 32610, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA., Robino RA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA., Castro-Gutierrez R; Diabetes Institute, University of Florida, Gainesville, FL 32610, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA., Proia J; Diabetes Institute, University of Florida, Gainesville, FL 32610, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA., Russ HA; Diabetes Institute, University of Florida, Gainesville, FL 32610, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA. Electronic address: holger.russ@ufl.edu., Ferreira LMR; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: ferreirl@musc.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Nov 26; Vol. 43 (11), pp. 114994. Date of Electronic Publication: 2024 Nov 18.
DOI:	10.1016/j.celrep.2024.114994
Abstrakt:	Regenerative medicine is a rapidly expanding field harnessing human pluripotent stem cell (hPSC)-derived cells and tissues to treat many diseases, including type 1 diabetes. However, graft immune protection remains a key challenge. Chimeric antigen receptor (CAR) technology confers new specificities to effector T cells and immunosuppressive regulatory T cells (Tregs). One challenge in CAR design is identifying target molecules unique to the cells of interest. Here, we employ combinatorial genetic engineering to confer CAR-Treg-mediated localized immune protection to stem cell-derived cells. We engineered hPSCs to express truncated epidermal growth factor receptor (EGFRt), a biologically inert and generalizable target for CAR-Treg homing and activation, and generated CAR-Tregs recognizing EGFRt. Strikingly, CAR-Tregs suppressed innate and adaptive immune responses in vitro and prevented EGFRt-hPSC-derived pancreatic beta-like cell (sBC [stem cell-derived beta cell]) graft immune destruction in vivo. Collectively, we provide proof of concept that hPSCs and Tregs can be co-engineered to protect hPSC-derived cells from immune rejection upon transplantation. Competing Interests: Declaration of interests A provisional patent on the strategy described in this article has been submitted with L.M.R.F. and H.A.R. as inventors. L.M.R.F. is an inventor in and has received royalties from patents on genetically modified human stem cells and T cells and consults for Guidepoint Global and McKesson. H.A.R. holds patents in the regenerative medicine space and served as a science advisory board (SAB) member of Sigilon Therapeutics and Prellis Biologics and consults or has consulted for Sigilon Therapeutics, Eli Lilly, Minutia, Guidepoint Global, Axon Advisors, and Tolerance Bio. H.A.R. is a scientific cofounder of Tolerance Bio. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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