Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

Abstract

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. 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 anti-tumor function, highlighting therapeutic avenues to improve T-cell based immunotherapy in the clinic.