Huang et al. demonstrated that pristane and its derivatives NJNU-0069 and NJNU-0069-003 induced MHC-II expression in cancer cells to potentiate antigen presentation and immune detection, which increased T cell infiltration and antitumor immunity in animal models of breast cancer. Fatty acid synthase (FASN)-catalyzed de novo fatty acid synthesis repressed MHC-II expression in cancer cells, leading to immune evasion. Pristane and its derivatives directly bound to the malonyl/acetyltransferase (MAT) domain in FASN and induced MHC-II expression in cancer cells, directly linking cancer metabolic reprogramming to immune evasion.
Contributed by Shishir Pant
ABSTRACT: Lack of MHC-II is emerging as a causal factor in cancer immune evasion, and the development of small-molecule MHC-II inducers is an unmet clinical need. Here, we identified three MHC-II inducers, including pristane and its two superior derivatives, that potently induce MHC-II expression in breast cancer cells and effectively inhibit the development of breast cancer. Our data suggest that MHC-II is central in promoting the immune detection of cancer to increase the tumor infiltration of T cells and enhance anti-cancer immunity. By discovering the malonyl/acetyltransferase (MAT) domain in fatty acid synthase (FASN) as the direct binding target of MHC-II inducers, we demonstrate that evasion of immune detection and cancer metabolic reprogramming are directly linked by fatty acid-mediated MHC-II silencing. Collectively, we identified three MHC-II inducers and illustrated that lack of MHC-II caused by hyper-activated fatty acid synthesis to limit immune detection is a potentially widespread mechanism underlying the development of cancer.
Author Info: (1) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nan
Author Info: (1) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. (2) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. (3) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. (4) Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. (5) State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210023, China. (6) Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. (7) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. (8) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. (9) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. (10) Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA. (11) State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210023, China. Electronic address: xiaojunxu@cpu.edu.cn. (12) Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: xielg@njnu.edu.cn. (13) Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. Electronic address: chenliming1981@njnu.edu.cn.
