Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

Research output: Contribution to journalArticle

Xingzhe Ma, Enguang Bi, Yong Lu, Pan Su, Chunjian Huang, Lintao Liu, Qiang Wang, Maojie Yang, Matthew F. Kalady, Jianfei Qian, Aijun Zhang, Anisha A. Gupte, Dale J. Hamilton, Chengyun Zheng, Qing Yi

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.

Original languageEnglish (US)
Pages (from-to)143-156.e5
JournalCell Metabolism
Volume30
Issue number1
Early online dateApr 18 2019
DOIs
StatePublished - Jul 2 2019

PMID: 31031094

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Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment. / 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.

In: Cell Metabolism, Vol. 30, No. 1, 02.07.2019, p. 143-156.e5.

Research output: Contribution to journalArticle

Harvard

Ma, X, Bi, E, Lu, Y, Su, P, Huang, C, Liu, L, Wang, Q, Yang, M, Kalady, MF, Qian, J, Zhang, A, Gupte, AA, Hamilton, DJ, Zheng, C & Yi, Q 2019, 'Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment' Cell Metabolism, vol. 30, no. 1, pp. 143-156.e5. https://doi.org/10.1016/j.cmet.2019.04.002

APA

Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., ... Yi, Q. (2019). Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment. Cell Metabolism, 30(1), 143-156.e5. https://doi.org/10.1016/j.cmet.2019.04.002

Vancouver

Ma X, Bi E, Lu Y, Su P, Huang C, Liu L et al. Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment. Cell Metabolism. 2019 Jul 2;30(1):143-156.e5. https://doi.org/10.1016/j.cmet.2019.04.002

Author

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. / Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment. In: Cell Metabolism. 2019 ; Vol. 30, No. 1. pp. 143-156.e5.

BibTeX

@article{576ea6eb42584caaa9c7bc16c2779883,
title = "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 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.",
keywords = "CD8+ T cells, cholesterol, exhaustion, immune checkpoints, tumor microenvironment",
author = "Xingzhe Ma and Enguang Bi and Yong Lu and Pan Su and Chunjian Huang and Lintao Liu and Qiang Wang and Maojie Yang and Kalady, {Matthew F.} and Jianfei Qian and Aijun Zhang and Gupte, {Anisha A.} and Hamilton, {Dale J.} and Chengyun Zheng and Qing Yi",
note = "Copyright {\circledC} 2019 Elsevier Inc. All rights reserved.",
year = "2019",
month = "7",
day = "2",
doi = "10.1016/j.cmet.2019.04.002",
language = "English (US)",
volume = "30",
pages = "143--156.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",

}

RIS

TY - JOUR

T1 - Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment

AU - Ma, Xingzhe

AU - Bi, Enguang

AU - Lu, Yong

AU - Su, Pan

AU - Huang, Chunjian

AU - Liu, Lintao

AU - Wang, Qiang

AU - Yang, Maojie

AU - Kalady, Matthew F.

AU - Qian, Jianfei

AU - Zhang, Aijun

AU - Gupte, Anisha A.

AU - Hamilton, Dale J.

AU - Zheng, Chengyun

AU - Yi, Qing

N1 - Copyright © 2019 Elsevier Inc. All rights reserved.

PY - 2019/7/2

Y1 - 2019/7/2

N2 - 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.

AB - 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.

KW - CD8+ T cells

KW - cholesterol

KW - exhaustion

KW - immune checkpoints

KW - tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85067358108&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067358108&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2019.04.002

DO - 10.1016/j.cmet.2019.04.002

M3 - Article

VL - 30

SP - 143-156.e5

JO - Cell Metabolism

T2 - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 1

ER -

ID: 48495107