TY - JOUR
T1 - Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment
AU - Lin, Zhiqing
AU - Huang, Keke
AU - Guo, Hui
AU - Jia, Manli
AU - Sun, Qiuqin
AU - Chen, Xuhao
AU - Wu, Jianmin
AU - Yao, Qingqing
AU - Zhang, Peng
AU - Vakal, Sergii
AU - Zou, Zhengzhi
AU - Gao, Haiyao
AU - Ci, Lei
AU - Chen, Jiangfan
AU - Guo, Wei
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (Grant No. 31970948 ), the Research Fund for International Senior Scientists of China (Grant No. 82150710558 ) and the Project of State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University , China ( J01-20190101 ). We thank Dr. Zheng Wu, Dr. Xuzhao Zhou, Dr. Tao Xu, and Dr. Chun Hu for the thought-provoking discussion of our research.
Publisher Copyright:
© 2023 The Authors
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - Nanoparticle
KW - Pancreatic cancer
KW - PD-L1
KW - Tumor microenvironment
KW - ZDHHC9
UR - http://www.scopus.com/inward/record.url?scp=85150445602&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2023.114567
DO - 10.1016/j.biopha.2023.114567
M3 - Article
AN - SCOPUS:85150445602
SN - 0753-3322
VL - 161
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 114567
ER -