Abstract
Tumor-infiltrating Tcells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8+ Tcell expression of immune checkpoints and exhaustion.Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8+ Tcells were positively and progressively associated with upregulated Tcell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8+ Tcells 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+ Tcells. Consequently, the ER stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8+ Tcells effectively restored antitumor activity. This study reveals a mechanism underlying Tcell exhaustion and suggests a new strategy for restoring Tcell function by reducing cholesterol to enhance Tcell-based immunotherapy.
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