Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China.
Mol Ther. 2023 Oct 4;31(10):2929-2947. doi: 10.1016/j.ymthe.2023.07.021. Epub 2023 Jul 28.
Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.
胰腺导管腺癌 (PDAC) 对免疫检查点阻断治疗不敏感，而肿瘤免疫逃逸的负反馈可能是部分原因。我们分离了 CD8+T 细胞并在体外培养。进行蛋白质组学分析以比较用条件培养基培养的 Panc02 细胞系的变化，鉴定出富含亮氨酸重复激酶 2 (LRRK2) 作为差异基因。LRRK2 的表达与 PDAC 临床样本中 CD8+T 细胞的空间分布有关，并通过体外 CD8+T 细胞模拟干扰素 γ (IFN-γ) 而上调。LRRK2 的敲低或药理学抑制在小鼠中激活了抗胰腺癌免疫反应，这意味着 LRRK2 作为一种免疫抑制基因发挥作用。从机制上讲，LRRK2 在 T210 处磷酸化 PD-L1 以抑制其泛素化介导的蛋白酶体降解。LRRK2 抑制减弱了 PD-1/PD-L1 阻断介导的、T 细胞诱导的 LRRK2/PD-L1 的上调，从而使小鼠对抗 PD-L1 治疗敏感。此外，发现维生素 B12 的活性形式腺苷钴胺素是 LRRK2 的广谱抑制剂，可在体内抑制 LRRK2 并使 PDAC 对免疫治疗敏感，这可能使 LRRK2 抑制具有临床转化价值。因此，PD-L1 阻断联合 LRRK2 抑制可能成为 PDAC 的一种新的治疗策略。
