Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4<sup>+</sup> T cells.

Details

Serval ID
serval:BIB_D26F38B87AE4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4<sup>+</sup> T cells.
Journal
Science advances
Author(s)
Rath J.A. (co-first), Bajwa G. (co-first), Carreres B., Hoyer E., Gruber I., Martínez-Paniagua M.A., Yu Y.R., Nouraee N., Sadeghi F., Wu M., Wang T., Hebeisen M., Rufer N., Varadarajan N., Ho P.C., Brenner M.K., Gfeller D., Arber C.
ISSN
2375-2548 (Electronic)
ISSN-L
2375-2548
Publication state
Published
Issued date
07/2020
Peer-reviewed
Oui
Volume
6
Number
27
Pages
eaaz7809
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Transgenic coexpression of a class I-restricted tumor antigen-specific T cell receptor (TCR) and CD8αβ (TCR8) redirects antigen specificity of CD4 <sup>+</sup> T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4 <sup>+</sup> T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8 <sup>+</sup> T cell function and preserved less differentiated CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells after tumor challenge. TCR8 <sup>+</sup> CD4 <sup>+</sup> T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation- and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.
Keywords
TCR, single-cell, T cell engineering, immunotherapy, leukemia
Pubmed
Web of science
Open Access
Yes
Create date
19/09/2020 11:28
Last modification date
23/10/2020 5:23
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