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Cancer Sci. 2018 Dec;109(12):3737-3750. doi: 10.1111/cas.13827. Epub 2018 Nov 2.

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction.

Author information

1
Department of Hematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Toon, Japan.
2
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Toon, Japan.
3
Department of Medical Technology, Ehime Prefectural University of Health Sciences, Tobe, Japan.
4
Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Japan.
5
Devision of Immune Regulation, Department of Proteo-Innovation, Proteo-Science Center, Ehime University, Toon, Japan.
6
Translational Research Center, Ehime University Hospital, Toon, Japan.
7
Department of Ophthalmology, Graduate School of Medicine, Ehime University, Toon, Japan.
8
Department of Obstetrics and Gynecology, Graduate School of Medicine, Ehime University, Toon, Japan.

Abstract

The antitumor activity of activated CD8+ T cells in the tumor microenvironment seems to be limited due to their being metabolically unfit. This metabolic unfitness is closely associated with T-cell exhaustion and impairment of memory formation, which are barriers to successful antitumor adoptive immunotherapy. We therefore assessed the role of glutamine metabolism in the antitumor activity of CD8+ T cells using a tumor-inoculated mouse model. The adoptive transfer of tumor-specific CD8+ T cells cultured under glutamine-restricted (dGln) conditions or CD8+ T cells treated with specific inhibitors of glutamine metabolism efficiently eliminated tumors and led to better survival of tumor-inoculated mice than with cells cultured under control (Ctrl) conditions. The decreased expression of PD-1 and increased Ki67 positivity among tumor-infiltrating CD8+ T cells cultured under dGln conditions suggested that the inhibition of glutamine metabolism prevents CD8+ T-cell exhaustion in vivo. Furthermore, the transferred CD8+ T cells cultured under dGln conditions expanded more efficiently against secondary OVA stimulation than did CD8+ T cells under Ctrl conditions. We found that the expression of a pro-survival factor and memory T cell-related transcription factors was significantly higher in CD8+ T cells cultured under dGln conditions than in those cultured under Ctrl conditions. Given these findings, our study uncovered an important role of glutamine metabolism in the antitumor activity of CD8+ T cells. The novel adoptive transfer of tumor-specific CD8+ T cells cultured in glutamine-restricted conditions may be a promising approach to improve the efficacy of cell-based adoptive immunotherapy.

KEYWORDS:

CD8+ T cells; T cell memory; adoptive immunotherapy; antitumor; glutaminnolysis

PMID:
30302856
PMCID:
PMC6272119
DOI:
10.1111/cas.13827
[Indexed for MEDLINE]
Free PMC Article

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