Chenqi Xu's group reveals a new way to potentiate T-cell antitumor immunity
2016-03-17 page view:6033
Chenqi Xu's group
On March 17, 2016 (Beijing time), Nature online publishes a research paper entitled “Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism”, from Prof. Chenqi Xu’s group and Prof. Bo-liang Li’s group of Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The authors found that inhibiting cholesterol esterification can potentiate the antitumor activity of CD8+ T cells (also known as killer T cells). This new way of improving T cell function might be used as a complement to current cancer immunotherapies, such as immune checkpoint blockade.
As key players of the immune system, T cells provide tumor surveillance and have direct antitumor effects. On the other hand, tumors can escape T-cell attack through various mechanisms in the tumor microenvironment. Reactivating the antitumor effects of T cells has shown great clinical benefits in treating various cancers. The current T cell-based cancer immunotherapies are nevertheless only effective to a limited group of patients. New cancer immunotherapies therefore need to be developed to benefit more patients.
Prof. Chenqi Xu’s group and Prof. Bo-liang Li’s group investigated T-cell antitumor immunity from a new perspective. They believe that modulating T-cell metabolism can make killer T cells more ‘metabolically fit’ to fight with tumor cells. As a key component of membrane lipids, cholesterol is important for T cell signalling and function. The researchers found that inhibiting a cholesterol esterification enzyme ACAT1 can increase the plasma membrane cholesterol level and therefore promote T-cell signalling and killing process. A small molecule inhibitor of ACAT1, avasimibe, was used to treat cancer in mouse tumor models and showed good antitumor effect. A combination of avasimibe and anti-PD-1 antibody, a checkpoint blockade drug, showed even better antitumor effect. This study opens a new field of cancer immune therapy and identifies ACAT1 as a promising drug target. It is worthy to mention that avasimibe was tested in clinical trials to treat atherosclerosis and had good human safety profile. Therefore, avasimibe could be a good drug candidate for cancer immunotherapy.
Other researchers from China and USA also contribute to this work. They are Dr. Xiaolong Liu from SIBCB, Dr. Wanli Liu from Tsinghua University, Dr. Bao-liang Song from Wuhan University, Dr. Penghui Zhou from Sun Yat-sen University Cancer Center, Dr. Shao-cong Sun from The University of Texas MD Anderson Cancer Center, and Dr. Ta-Yuan Chang from Geisel School of Medicine at Dartmouth. This work was supported by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, and Shanghai Science and Technology Committee. This work was also technically supported by the Integrated Laser Microscopy Facility at National Center for Protein Science Shanghai, SIBCB Animal Core Facility, Cell Biology Core Facility and Molecular Biology Core Facility.
A cartoon illustration on novel method of tumor therapy