Cholesterol induces CD8+ T-cell exhaustion in the tumor microenvironment
By Xingzhe Ma, Enguang Bi, Yong Lu, Pan Su, Chunjian Huang, Lintao Liu, Qiang Wang, Maojie Yang, M. Kalady, J. Qian and 5 more. Cell Metabolism, 2019
868 citations recorded by the source corpus.
SUMMARY 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 was 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 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 novel mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T-cell based immunotherapy.
Subfields: Cancer Research, Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/0df0201db15e212951508389100fb835845699ab
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Citations in the corpus
- Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer. (2019, background): “Moreover, increased amounts of cholesterol in the tumor microenvironment was recently shown to induce exhaustion in CD8+ T cells (Ma et al., 2019).”
- The updated landscape of tumor microenvironment and drug repurposing (2020, background): “In a murine melanoma model, cholesterol increases endoplasmic reticulum stress, activates X-box binding protein 1 (XBP1), and upregulates PD-1 expression on CD8 T cells, indicating that the combination of immunotherapy and cholesterol-reducing therapy may have great benefits.(96) Strikingly, lipid m”