Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism

By Wei Yang, Yibing Bai, Y. Xiong, Jin Zhang, Shuokai Chen, Xiaojun Zheng, Xiangbo Meng, Lunyi Li, Jing Wang, Chenguang Xu and 12 more. Nature, 2016

892 citations recorded by the source corpus.

CD8+ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8+ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8+ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8+ but not CD4+ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8+ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8+ T cells were better than wild-type CD8+ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/152d222a7ecff3d7a211d8ac522c00a447cfc3b4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. Lichtman
2. Michael D. Buck
3. S. Kaech
4. R. Sowell
5. Erika L. Pearce
6. I. Tabas
7. Rafi Ahmed
8. E. Wherry

In Oncology

1. R. Sowell
2. Erika L. Pearce
3. S. Kaech
4. I. Tabas
5. A. Lichtman
6. Michael D. Buck

Citations in the corpus

• Metabolic Instruction of Immunity (2017, positive): “In addition, blocking cholesterol esterification in TILs by targeting ACAT1 pharmacologically or genetically increases intracellular levels of cholesterol and confers superior T cell responses in a model of melanoma (Yang et al., 2016).”
• Monocyte-Macrophages and T Cells in Atherosclerosis (2017, positive): “This was shown to be the case for CD8 Teff cells in mice in which cellular unesterified cholesterol was elevated by interventions that block the formation of cholesteryl ester (Yang et al., 2016).”