Efficient T cell adoptive transfer in lymphoreplete hosts mediated by transient activation of Stat5 signaling.

Autor:	Tennant MD; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Charleston, SC 29425, USA; Ralph H. Johnson VA Medical Center, Charleston, SC 29425, USA., New C; Hollings Cancer Center, Charleston, SC 29425, USA; Department of Pediatric Medicine, Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, USA., Ferreira LMR; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Charleston, SC 29425, USA; Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA., O'Neil RT; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Charleston, SC 29425, USA; Ralph H. Johnson VA Medical Center, Charleston, SC 29425, USA. Electronic address: oneilr@musc.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Sep 06; Vol. 31 (9), pp. 2591-2599. Date of Electronic Publication: 2023 Jul 21.
DOI:	10.1016/j.ymthe.2023.07.015
Abstrakt:	Lymphodepleting pre-conditioning is a nearly universal component of T cell adoptive transfer protocols. The side effects of pre-conditioning regimens used in adoptive cell therapy are clinically significant and include pan-cytopenia, immune suppression, and reactive myelopoiesis. We conducted studies to test the hypothesis that the mechanisms underlying effective engraftment are cell autonomous and not dependent on a lymphodepleted host immune status. These studies leveraged mouse models to examine the role of Stat5 signaling during T cell adoptive transfer. We observed that, by transiently expressing a constitutively active mutamer of Stat5b during the process of adoptive transfer, we could completely obviate the need for lymphodepletion prior to adoptive transfer. Using several functional assays, we benchmark the function of the engrafted T cells against T cells transferred after conventional lymphodepletion. These studies identify a cell-autonomous mechanism driven by transient Stat5b signaling with lasting effects on T cell phenotype and function. Furthermore, the results presented suggest that adoptive T cell therapy could be improved by removing lymphodepletion protocols entirely and replacing them with RNA transfection of T cells with transcripts encoding active Stat5. Competing Interests: Declaration of interests A provisional patent based on results from this work has been filed by M.D.T. and R.T.O. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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