IMR Press / FBL / Volume 27 / Issue 8 / DOI: 10.31083/j.fbl2708243
Open Access Original Research
Dysfunction of Cytotoxic T Lymphocyte Induced by Hepatoma Cells through the Gln-GLS2-Endoplasmic Reticulum Stress Pathway
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1 Laboratory Department, Tangshan Maternal and Child Health Care Hospital Affiliated to North China University of Science and Technology, 063000 Tangshan, Hebei, China
*Correspondence: (Jinghua Wu)
Academic Editor: Taeg Kyu Kwon
Front. Biosci. (Landmark Ed) 2022, 27(8), 243;
Submitted: 9 June 2022 | Revised: 18 July 2022 | Accepted: 26 July 2022 | Published: 15 August 2022
(This article belongs to the Special Issue New Frontiers in Vascular Remodeling)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Metabolic activities of tumor cells lead to a depletion of nutrients within the tumor microenvironment, which results in the dysfunction of infiltrating T cells. Here, we explored how glutamine (gln) metabolism, which is essential for biosynthesis and cellular function, can affect the functions of cytotoxic T lymphocytes (CTLs). Methods: Activated CTLs were co-cultured with hepatoma cells. Western blot was used to analyze changes of proteins and ELISA was used to analyze changes of effector. RNA-sequencing was used to detect differentially expressed genes in CTLs. The status of the endoplasmic reticulum (ER) was investigated using transmission electron microscopy experiments. Results: Co-culturing CTLs and hepatoma cells revealed that CTLL-2 cells in the co-culture group expressed high levels of PD-1 (Programmed cell death protein 1), TIM-3 (T cell immunoglobulin and mucin domain-containing protein-3), GRP78 (Glucose regulated protein 78), and P-PERK (phosphorylated protein kinase RNA-activated-like endoplasmic reticulum kinase) and secreted low levels of Granzyme B and perforin. Additionally, the substructure of the ER was severely damaged. When CTLs were treated with an inhibitor of ER stress, their functions were restored. Next, complete medium without Gln was used to culture cells, causing CTLs to display dysfunction and ER stress. WB results revealed decreased expression levels of GLS2 and SLC1A5 (Solute carrier family 1 member 5) in CTLs in the co-culture group. Subsequently, glutaminase (GLS) inhibitors were added to the cultures. As expected, CTLs treated with a GLS2 inhibitor had increased protein content of PD-1 and TIM-3, decreased secretion of Granzyme B and perforin, and an enhanced ER stress response. Conclusions: In summary, CTLs are functionally downregulated induced by hepatoma cells through the Gln-GLS2-ERS pathway.

endoplasmic reticulum stress
A202003005/High-End Talent Funding Project in Hebei Province
G2019074/Hebei Provincial Health Commission Office
H2019209355/Natural Science Foundation of Hebei Province
Fig. 1.
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