Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100864, China.
Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Cell Immunol. 2021 Apr;362:104286. doi: 10.1016/j.cellimm.2021.104286. Epub 2021 Jan 19.
Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumor-infiltrating CD8T-cells. Furthermore, the combination therapy blocked MDSC's suppressive role on T- cells thereby enhanced T-cell's ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid accumulation-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.
尽管 PD-1/PD-L1 轴的免疫检查点阻断（ICB）疗法取得了显著的成功和疗效，但由于髓系来源的抑制细胞（MDSCs）等免疫抑制因子的激活，它仅能使相当一部分癌症患者产生持续的反应。抑制 MDSCs 的免疫抑制功能对于成功的癌症 ICB 治疗至关重要。有趣的是，脂质代谢是调节 MDSCs 功能的关键因素。脂肪酸转运蛋白 2（FATP2）通过上调花生四烯酸代谢赋予 PMN-MDSCs 在癌症中的功能。然而，通过靶向 FATP2 调节 MDSCs 中的脂质积累是否可以阻断 MDSCs 活性氧（ROS）的产生并增强 PD-L1 阻断介导的肿瘤免疫治疗仍未可知。在这里，我们报告 FATP2 调节荷瘤小鼠中 MDSCs 的脂质积累、ROS 和免疫抑制功能。肿瘤细胞衍生的粒细胞-巨噬细胞集落刺激因子（GM-CSF）通过激活 STAT3 信号通路诱导 MDSCs 中 FATP2 的表达。通过 lipofermata 抑制 MDSCs 中 FATP2 的药物表达可减少脂质积累，降低 ROS，阻断免疫抑制活性，从而抑制肿瘤生长。更重要的是，lipofermata 抑制 MDSCs 中的 FATP2 通过上调 CD107a 和降低肿瘤浸润 CD8T 细胞上的 PD-L1 表达来增强抗 PD-L1 肿瘤免疫治疗。此外，联合治疗阻断 MDSC 对 T 细胞的抑制作用，从而增强 T 细胞产生 IFN-γ 的能力。这些发现表明 FATP2 在调节 MDSCs 中脂质积累诱导的 ROS 中发挥关键作用，靶向 MDSCs 中的 FATP2 为增强抗 PD-L1 癌症免疫治疗提供了一种新的治疗方法。
