Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

• Published in: Cell metabolism Vol. 30; no. 1; pp. 143 - 156.e5
• Main Authors: Ma, Xingzhe, Bi, Enguang, Lu, Yong, Su, Pan, Huang, Chunjian, Liu, Lintao, Wang, Qiang, Yang, Maojie, Kalady, Matthew F., Qian, Jianfei, Zhang, Aijun, Gupte, Anisha A., Hamilton, Dale J., Zheng, Chengyun, Yi, Qing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.07.2019
• Subjects: CD8+ T cells; cholesterol; exhaustion; immune checkpoints; tumor microenvironment; exhaustion; CD8+ T cells; cholesterol; tumor microenvironment; immune checkpoints
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2019.04.002

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 checkpoints, 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. [Display omitted] •CD8+ T cell exhaustion is correlated with a high cholesterol level•Tumor microenvironment is enriched with cholesterol•Cholesterol in the tumor microenvironment induces CD8+ T cell exhaustion•ER stress-XBP1 pathway is required for cholesterol-induced CD8+ T cell exhaustion Tumor-infiltrating T cells often lose their effector function. Ma et al. show that cholesterol in the tumor microenvironment induces CD8+ T cell exhaustion in an ER-stress-XBP1-dependent manner. Reducing cholesterol or ER stress enhanced CD8+ T cell antitumor function, highlighting therapeutic avenues to improve T cell-based immunotherapy in the clinic.