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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Wang X,Hu LP,Qin WT,Yang Q,Chen DY,Li Q,Zhou KX,Huang PQ,Xu CJ,Li J,Yao LL,Wang YH,Tian GA,Yang JY,Yang MW,Liu DJ,Sun YW,Jiang SH,Zhang XL,Zhang ZGdoi
10.1038/s41467-020-20447-ysubject
Has Abstractpub_date
2021-01-08 00:00:00pages
174issue
1issn
2041-1723pii
10.1038/s41467-020-20447-yjournal_volume
12pub_type
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