Cholesterol Induces CD8 T Cell Exhaustion in the Tumor Microenvironment.

Cell Metab 2019 Jul 25;30(1):143-156.e5. Epub 2019 Apr 25.

Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address:

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2019.04.002DOI Listing
July 2019
4 Reads

Publication Analysis

Top Keywords

cd8 t cells
16
immune checkpoints
8
t cell expression
8
tumor microenvironment
8
cholesterol
8
pd-1 2b4
8
reducing cholesterol
8
induces cd8
8
cd8
6
t cells
5
immune checkpoint
4
induced immune
4
cholesterol induced
4
supernatant cholesterol
4
expression increasing
4
reticulum stress
4
stress cd8
4
endoplasmic reticulum
4
increasing endoplasmic
4
culture supernatant
4

Altmetric Statistics

110 Tweets

Similar Publications