As key players in the immune system, T cells provide tumor surveillance and have direct antitumor effects. However, 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 in a limited group of patients. New cancer immunotherapies are needed, therefore, to benefit more patients.
In their new study, Prof. XU Chenqi's group and Prof. LI Boliang's group with the Institute of Biochemistry and Cell Biology (SIBCB) of the Shanghai Institutes for Biological Sciences, 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.
Their research, entitled "Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism," was published in Nature on March 17.
The researchers 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 tumor cells. As a key component of membrane lipids, cholesterol is important for T-cell signaling and function.
Scientists found that inhibiting the cholesterol esterification enzyme ACAT1 can increase the plasma membrane cholesterol level and therefore promote the T-cell signaling 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 immunotherapy and identifies ACAT1 as a promising drug target. It is worth mentioning that avasimibe was tested in clinical trials to treat atherosclerosis and had a good human safety profile. Therefore, avasimibe could be a good drug candidate for cancer immunotherapy.
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Other researchers from China and the USA also contributed to this work. They are Dr. LIU Xiaolong of SIBCB, Dr. LIU Wanli of Tsinghua University, Dr. SONG Baoliang of Wuhan University, Dr. ZHOU Penghui of Sun Yat-sen University Cancer Center, Dr. Shao-cong Sun of The University of Texas MD Anderson Cancer Center, and Dr. Ta-Yuan Chang of the 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 the Science and Technology Commission of Shanghai Municipality.
This work was also technically supported by the Integrated Laser Microscopy Facility at the National Center for Protein Science Shanghai, the SIBCB Animal Core Facility, the Cell Biology Core Facility, and the Molecular Biology Core Facility.
Journal
Nature