Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis

Xu Wang, Li-Peng Hu, Wei-Ting Qin, Qin Yang, Chen De-Yu, Qing Li, Kai-Xia Zhou, Pei-Qi Huang, Chun-Jie Xu, Jun Li, Lin-Li Yao, Ya-Hui Wang, Guang-Ang Tian, Jian-Yu Yang, Min-Wei Yang, Liu De-Jun, Yong-Wei Sun (), Shu-Heng Jiang (), Xue-Li Zhang () and Zhi-Gang Zhang ()
Additional contact information
Xu Wang: Shanghai Jiao Tong University
Li-Peng Hu: Shanghai Jiao Tong University
Wei-Ting Qin: Shanghai Jiao Tong University
Qin Yang: Shanghai Jiao Tong University
Chen De-Yu: Affiliated Hospital of Jiangsu University
Qing Li: Shanghai Jiao Tong University
Kai-Xia Zhou: Shanghai Jiao Tong University
Pei-Qi Huang: Shanghai Jiao Tong University
Chun-Jie Xu: Shanghai Jiao Tong University
Jun Li: Shanghai Jiao Tong University
Lin-Li Yao: Shanghai Jiao Tong University
Ya-Hui Wang: Shanghai Jiao Tong University
Guang-Ang Tian: Shanghai Jiao Tong University
Jian-Yu Yang: Shanghai Jiao Tong University
Min-Wei Yang: Shanghai Jiao Tong University
Liu De-Jun: Shanghai Jiao Tong University
Yong-Wei Sun: Shanghai Jiao Tong University
Shu-Heng Jiang: Shanghai Jiao Tong University
Xue-Li Zhang: Shanghai Jiao Tong University
Zhi-Gang Zhang: Shanghai Jiao Tong University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.

Date: 2021
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DOI: 10.1038/s41467-020-20447-y

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