Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment

Zhiqing Lin, Keke Huang, Hui Guo, Manli Jia, Qiuqin Sun, Xuhao Chen, Jianmin Wu, Qingqing Yao, Peng Zhang, Sergii Vakal, Zhengzhi Zou, Haiyao Gao, Lei Ci, Jiangfan Chen*, Wei Guo

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

7 Citations (Scopus)
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Abstract

Immune checkpoint blockade (ICB) therapy targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) axis has achieved considerable success in treating a wide range of cancers. However, most patients with pancreatic cancer remain resistant to ICB. Moreover, there is a lack of optimal biomarkers for the prediction of response to this therapy. Palmitoylation is mediated by a family of 23 S-acyltransferases, termed zinc finger Asp‐His‐His‐Cys-type palmitoyltransferases (ZDHHC), which precisely control various cancer-related protein functions and represent promising drug targets for cancer therapy. Here, we revealed that tumor cell-intrinsic ZDHHC9 was overexpressed in pancreatic cancer tissues and associated with impaired anti-tumor immunity. In syngeneic pancreatic tumor models, the knockdown of ZDHHC9 expression suppressed tumor progression and prolonged survival time of mice by modifying the immunosuppressive (‘cold’) to proinflammatory (‘hot’) tumor microenvironment. Furthermore, ZDHHC9 deficiency sensitized anti-PD-L1 immunotherapy mainly in a CD8+ T cell dependent manner. Lastly, we employed the ZDHHC9-siRNA nanoparticle system to efficiently silence ZDHHC9 in pancreatic tumors. Collectively, our findings indicate that ZDHHC9 overexpression in pancreatic tumors is a mechanism involved in the inhibition of host anti-tumor immunity and highlight the importance of inactivating ZDHHC9 as an effective immunotherapeutic strategy and booster for anti-PD-L1 therapy against pancreatic cancer.

Original languageEnglish
Article number114567
JournalBiomedicine and Pharmacotherapy
Volume161
DOIs
Publication statusPublished - May 2023
MoE publication typeA1 Journal article-refereed

Keywords

  • Immunotherapy
  • Nanoparticle
  • Pancreatic cancer
  • PD-L1
  • Tumor microenvironment
  • ZDHHC9

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