Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy

• DOI: 10.1016/j.ymthe.2023.07.021
• Publication Date: 2023-07-28T01:13:27Z
• Authors: Kang Sun; Xiaozhen Zhang; Mengyi Lao; Lihong He; Sicheng Wang; Hanshen Yang; Jian Xu; Jianghui Tang; Zhengtao Hong; Jinyuan Song; Chengxiang Guo; Muchun Li; Xinyuan Liu; Yan Chen; Hanjia Zhang; Jingxing Zhou; Jieru Lin; Sirui Zhang; Yifan Hong; Jinyan Huang; Tingbo Liang; Xueli Bai
• Keywords: AKT2

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor evasion might be partly responsible. We isolated CD8+ T cells cultured them in vitro. Proteomics analysis was performed compare changes Panc02 cell lines with conditioned medium, leucine-rich repeat kinase 2 (LRRK2) identified as a differential gene. LRRK2 expression related spatial distribution PDAC clinical samples upregulated by via interferon gamma (IFN-γ) simulation Knockdown or pharmacological inhibition activated an anti-pancreatic cancer response mice, which meant that acted immunosuppressive Mechanistically, phosphorylated PD-L1 at T210 inhibit its ubiquitination-mediated proteasomal degradation. attenuated PD-1/PD-L1 blockade-mediated, cell-induced upregulation LRRK2/PD-L1, thus sensitizing the mice anti-PD-L1 therapy. In addition, adenosylcobalamin, form vitamin B12, found broad-spectrum inhibitor LRRK2, could vivo sensitize immunotherapy well, potentially endows translational value. Therefore, combined novel therapy strategy for PDAC.