中山大学Jian Zheng和Dongxin Lin团队合作的最新研究发现，喹啉二氢蝶啶还原酶（QDPR）缺乏会导致胰腺癌免疫抑制。相关论文于2024年4月19日发表于国际学术期刊《细胞—代谢》杂志。

研究人员发现在胰腺导管腺癌（PDACs）患者中，调节生物蝶呤代谢的关键酶-QDPR缺乏会导致代谢产物二氢生物蝶呤（BH2）的积累，并降低四氢生物蝶呤（BH4）与BH2的比率。BH4/BH2比率降低导致活性氧（ROS）生成增加，CXCL1启动子区H3K27me3的分布减少。因此，髓源性抑制细胞通过CXCR2招募到肿瘤微环境中，导致对免疫检查点阻断疗法（ICB）治疗产生抗药性。

研究发现，补充BH4能够恢复BH4/BH2比率，增强抗肿瘤免疫力，克服QDPR缺乏PDAC患者对ICB的耐药性。QDPR表达较低的肿瘤对ICB治疗的反应性降低。这些发现为患者如何选择治疗方案提供了一种新策略，以提高ICB治疗PDAC的效果。

附：英文原文

Title: QDPR deficiency drives immune suppression in pancreatic cancer

Author: Ji Liu, Xiaowei He, Shuang Deng, Sihan Zhao, Shaoping Zhang, Ziming Chen, Chunling Xue, Lingxing Zeng, Hongzhe Zhao, Yifan Zhou, Ruihong Bai, Zilan Xu, Shaoqiu Liu, Quanbo Zhou, Mei Li, Jialiang Zhang, Xudong Huang, Rufu Chen, Liqin Wang, Dongxin Lin, Jian Zheng

Issue&Volume: 2024-04-19

Abstract: The relevance of biopterin metabolism in resistance to immune checkpoint blockade(ICB) therapy remains unknown. We demonstrate that the deficiency of quinoid dihydropteridinereductase (QDPR), a critical enzyme regulating biopterin metabolism, causes metabolitedihydrobiopterin (BH2) accumulation and decreases the ratio of tetrahydrobiopterin(BH4) to BH2 in pancreatic ductal adenocarcinomas (PDACs). The reduced BH4/BH2 ratioleads to an increase in reactive oxygen species (ROS) generation and a decrease inthe distribution of H3K27me3 at CXCL1 promoter. Consequently, myeloid-derived suppressorcells are recruited to tumor microenvironment via CXCR2 causing resistance to ICBtherapy. We discovered that BH4 supplementation is capable to restore the BH4/BH2ratio, enhance anti-tumor immunity, and overcome ICB resistance in QDPR-deficientPDACs. Tumors with lower QDPR expression show decreased responsiveness to ICB therapy.These findings offer a novel strategy for selecting patient and combining therapiesto improve the effectiveness of ICB therapy in PDAC.

DOI: 10.1016/j.cmet.2024.03.015

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00119-0