Journal Article

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

Bai, Yibing, Meng, Xiangbo, Chang, Ta-Yuan, Liu, Xiaolong, Li, Bo-liang, Xu, Chenqi, Xu, Chenguang, Chen, Shuokai, Wang, Jing, Chang, Catharine C. Y., Zhou, Penghui, Yang, Wei, Wang, Lijuan, Zhang, Ti, Zhang, Jin, Song, Bao-Liang, Yan, Chengsong, Liu, Wanli, Xiong, Ying, Sun, Shao-cong, Li, Lunyi, Zheng, Xiaojun

2016

Overview

Modulating cholesterol metabolism can improve CD8 + T-cell-mediated immunity against tumours; genetic or pharmacological inhibition of the cholesterol esterification enzyme ACAT1 led to higher plasma membrane cholesterol levels, better T-cell receptor clustering and signalling, improved immunological synapse maturation, and enhanced antitumour activity in mice. T cell antitumour activity boosted This study reports a new approach to cancer immunotherapy through the modulation of T cell cholesterol metabolism. Chenqi Xu and colleagues demonstrate that inhibition of the cellular cholesterol esterification pathway in mice, either by genetic ablation or by pharmacological inhibition of acetyl-CoA acetyltransferase 1 (ACAT1) and ACAT2, increases plasma membrane cholesterol levels, T-cell receptor clustering and signalling, and significantly potentiates the antitumour response of CD8 + T cells in mice. To test the potential of ACAT1 as a drug target for cancer immunotherapy, the authors treated melanoma-bearing mice with avasimibe, an ACAT inhibitor that has been used to treat atherosclerosis in clinical trials. An antitumour effect was observed and a combination of avasimibe and anti-PD-1 antibody was more effective than either alone. CD8 + T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment 1 , 2 , 3 , 4 . 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 5 , 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 6 , 7 , 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.

• Publisher: Nature Publishing Group UK
• Subject: 631/250/1619/554 / 631/250/251 / 631/250/580 / 631/443/319 / 631/67/580 / Acetates - pharmacology / Acetates - therapeutic use / Acetyl-CoA C-Acetyltransferase - antagonists & inhibitors / Acetyl-CoA C-Acetyltransferase - deficiency / Acetyl-CoA C-Acetyltransferase - genetics / Acetyl-CoA C-Acetyltransferase - metabolism / Animals / Atherosclerosis - drug therapy / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Membrane - drug effects / Cell Membrane - metabolism / Cholesterol - metabolism / Esterification - drug effects / Female / Humanities and Social Sciences / Immunological Synapses - drug effects / Immunological Synapses - immunology / Immunological Synapses - metabolism / Immunotherapy - methods / letter / Male / Melanoma - drug therapy / Melanoma - immunology / Melanoma - metabolism / Melanoma - pathology / Mice / multidisciplinary / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Science / Signal Transduction - drug effects / Sulfonic Acids - pharmacology / Sulfonic Acids - therapeutic use