期刊
CELL METABOLISM
卷 30, 期 1, 页码 143-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.04.002
关键词
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资金
- National Cancer Institute [R01 CA163881, R01 CA200539, R01 CA211073, R01 CA214811]
- Cancer Prevention AMP
- Research Institute of Texas (CPRIT) Recruitment of Established Investigator Award [RR180044]
- Research Core services in the Lerner Research Institute of the Cleveland Clinic
Tumor-infiltrating T cells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8(+) T cell expression of immune checkpoints and exhaustion. Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8(+) T cells were positively and progressively associated with upregulated T cell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8(+) T cells acquired cholesterol, expressed high levels of immune check-points, and became exhausted upon entering a tumor. Tumor culture supernatant or cholesterol induced immune checkpoint expression by increasing endoplasmic reticulum (ER) stress in CD8(+) T cells. Consequently, the ER stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8(+) T cells effectively restored antitumor activity. This study reveals a mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T cell-based immunotherapy.
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