Zhang Han, Chen Hui, Yin Shutao, Fan Lihong, Jin Caiwei, Zhao Chong, Hu Hongbo
College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.
College of Veterinary Medicine, China Agricultural University, Beijing, China.
J Nutr Biochem. 2023 Feb;112:109186. doi: 10.1016/j.jnutbio.2022.109186. Epub 2022 Oct 27.
PD-L1 interacts with its receptor PD-1 on T cells to negatively regulate T cell function, leading to cancer cell immune escape from the immune surveillance. Therefore, targeting PD-L1 is considered to be an attractive approach for cancer immunotherapy. In this study, we demonstrated for the first time that ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduced the expression of PD-L1 in cancer cells both in vitro and in vivo. Promotion of PD-L1 ubiquitin-proteasome degradation by DHA resulted in a decrease of PD-L1 expression, leading to reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. Furtherly, DHA significantly reduced fatty acid synthase (FASN) expression in cancer cells, which inhibited the palmitoyltransferases DHHC5, promoting the CSN5-dependent PD-L1 degradation. Our present finding uncovered a novel mechanism involved in the anti-cancer activity of DHA, and implicated that DHA holds promising potential to be developed as a novel immune-enhancer for cancer treatment and prevention.
程序性死亡配体1（PD-L1）与T细胞上的受体程序性死亡受体1（PD-1）相互作用，从而负向调节T细胞功能，导致癌细胞从免疫监视中实现免疫逃逸。因此，靶向PD-L1被认为是一种有吸引力的癌症免疫治疗方法。在本研究中，我们首次证明ω-3多不饱和脂肪酸（PUFA）二十二碳六烯酸（DHA）在体外和体内均可降低癌细胞中PD-L1的表达。DHA促进PD-L1泛素-蛋白酶体降解，导致PD-L1表达降低，进而减少PD-L1与PD-1的相互作用，并逆转PD-L1介导的免疫抑制，这反过来又有助于对肿瘤生长产生抑制作用。此外，DHA显著降低癌细胞中脂肪酸合酶（FASN）的表达，抑制棕榈酰转移酶DHHC5，促进CSN5依赖性的PD-L1降解。我们目前的发现揭示了DHA抗癌活性所涉及的一种新机制，并表明DHA具有作为癌症治疗和预防新型免疫增强剂开发的潜在前景。
