Abstract：
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.
摘要：
PD-L1与其T细胞上的受体PD-1相互作用，负向调节T细胞功能，导致癌细胞免疫逃避免疫监视。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.在这项研究中,我们首次证明ω-3多不饱和脂肪酸（PUFA）二十二碳六烯酸（DHA）在体外和体内均降低了PD-L1在癌细胞中的表达。DHA促进PD-L1泛素-蛋白酶体降解导致PD-L1表达减少，导致PD-L1和PD-1相互作用的减少，和逆转PD-L1介导的免疫抑制，这反过来又有助于对肿瘤生长的抑制作用。更进一步,DHA显著降低癌细胞中脂肪酸合成酶（FASN）的表达，抑制棕榈酰转移酶DHHC5，促进CSN5依赖性PD-L1降解。我们目前的发现揭示了参与DHA抗癌活性的新机制，并暗示DHA具有被开发为用于癌症治疗和预防的新型免疫增强剂的潜力。
