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

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.

C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1

“…Moreover, increased C5aR1 + neutrophils were linked to tumor progression and poor survival for BC patients. Similarly, a recent study identifies a unique neutrophil subclone that lacks P2RX1 and participates in immunosuppression and cancer metastasis [ 25 ]. These studies indicate that the characterization of different neutrophil subsets based on specific molecules can guide the development of neutrophil-targeting precision therapies.…”

Current Understanding of the Neutrophil Transcriptome in Health and Disease

“…Another study investigating development of liver metastases also analysed transcriptomic responses by neutrophils to cytokines. Mouse bone marrow neutrophils were stimulated with G-CSF, as well as lipopolysaccharide, interferon γ and IL-4 [117] and analysed by RNAseq. Wang and colleagues only reported differential expression of 19 genes for purinergic receptors dependent upon the stimulating cytokine [117].…”

Pancreatic cancer immune evasion mechanisms: the immunosuppressive role of P2RX1-negative neutrophils

“…Recent studies showed that liver metastatic PDAC contains exhausted CTLs, suggesting that targeting the immunosuppressive TME could be a promising strategy for treating liver metastasis of PDAC [6,8]. In the paper by Wang et al [1], the immunosuppressive TME in PDAC liver metastasis was found to be due mainly to the activity of a subset of neutrophils deficient in the purinergic receptor P2RX1 that accumulated in the presence of PDAC metastasis. Neutrophils are a critical component of the TME, with both antitumoural and protumoural activities.…”

“…However, in latestage cancers, this immune population displayed potent antitumour properties [9]. P2RX1-deficient neutrophils infiltrating PDAC liver metastasis facilitate the creation of an immunosuppressive microenvironment, inhibiting CTLs responses [1,10]. This subset of neutrophils up-modulate expression on their surface of immune escape and N2-like molecules, such as PD-L1, and reprogram their metabolism by switching towards an oxidative-mitochondrial metabolism that supports their immunosuppressive features.…”

“…An immunosuppressive microenvironment is essential to promote tumour immune evasion mechanisms, leading to tumour growth and metastatisation. In a recent study, Wang et al [1] demonstrated that neutrophils are a critical immune component of the PDAC liver metastatic tumour microenvironment (TME). Specifically, the authors showed that tumours evade antitumour immunity by accumulating a subset of purinergic receptor (P2RX1)-negative neutrophils.…”