Cystathionine-gamma-lyase overexpression in T cells enhances antitumor effect independently of cysteine autonomy.

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_145E54BFE34D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cystathionine-gamma-lyase overexpression in T cells enhances antitumor effect independently of cysteine autonomy.
Journal
Cancer science
Author(s)
Lancien M., Gueno L., Salle S., Merieau E., Beriou G., Nguyen T.H., Abidi A., Dilek N., Solomon P., Poschmann J., Michielin O., Vuillefroy de Silly R., Vanhove B., Louvet C.
ISSN
1349-7006 (Electronic)
ISSN-L
1347-9032
Publication state
Published
Issued date
05/2021
Peer-reviewed
Oui
Volume
112
Number
5
Pages
1723-1734
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
T cells could be engineered to overcome the aberrant metabolic milieu of solid tumors and tip the balance in favor of a long-lasting clinical response. Here, we explored the therapeutic potential of stably overexpressing cystathionine-gamma-lyase (CTH, CSE, or cystathionase), a pivotal enzyme of the transsulfuration pathway, in antitumor CD8 <sup>+</sup> T cells with the initial aim to boost intrinsic cysteine metabolism. Using a mouse model of adoptive cell transfer (ACT), we found that CTH-expressing T cells showed a superior control of tumor growth compared to control T cells. However, contrary to our hypothesis, this effect was not associated with increased T cell expansion in vivo or proliferation rescue in the absence of cysteine/cystine in vitro. Rather than impacting methionine or cysteine, ACT with CTH overexpression unexpectedly reduced glycine, serine, and proline concentration within the tumor interstitial fluid. Interestingly, in vitro tumor cell growth was mostly impacted by the combination of serine/proline or serine/glycine deprivation. These results suggest that metabolic gene engineering of T cells could be further investigated to locally modulate amino acid availability within the tumor environment while avoiding systemic toxicity.
Keywords
Adoptive Transfer/methods, Animals, CD8-Positive T-Lymphocytes/metabolism, Cell Engineering, Cell Line, Tumor, Cell Proliferation, Cystathionine gamma-Lyase/metabolism, Cysteine/biosynthesis, Extracellular Fluid/metabolism, Female, Glycine/metabolism, Methionine/metabolism, Mice, Mice, Inbred C57BL, Models, Animal, Ovarian Neoplasms/therapy, Proline/metabolism, Serine/metabolism, Tumor Microenvironment/immunology, T cell, adoptive cell transfer, amino acid, cysteine, metabolism
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2021 12:48
Last modification date
12/01/2022 7:08
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