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

Nat Commun. 2021 Jan 8;12(1):174. doi: 10.1038/s41467-020-20447-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Disease Models, Animal
  • Immunosuppressive Agents / pharmacology*
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Neutrophils / metabolism*
  • Pancreas / immunology
  • Pancreas / pathology
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Receptors, Purinergic P2X / genetics
  • Receptors, Purinergic P2X / immunology
  • Receptors, Purinergic P2X / metabolism
  • Tumor Microenvironment / immunology*

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Immunosuppressive Agents
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Receptors, Purinergic P2X