Neutrophils in pancreatic cancer: Potential therapeutic targets

Abstract

Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.

Keywords: anticancer therapy; neutrophil; neutrophil extracellular trap; pancreatic cancer; tumor-associated neutrophil.

Figure 1

Killing mechanisms of neutrophils. The killing mechanisms of neutrophils include both intracellular and extracellular mechanisms. Neutrophils can encase pathogens in the phagocytic body through phagocytosis and can also release particles into the extracellular environment that act on external pathogens. Meanwhile, normal tissues in the body can be attacked by neutrophils.

Figure 2

Impact of neutrophils on the progression and metastasis of pancreatic cancer. Obesity-induced inflammation and TAN infiltration activate PSCs, leading to connective tissue proliferation in the TME and promoting tumor growth. Conversely, PSCs can also recruit TANs. Neutrophils produce HMGB1 in pancreatic cancer, which induces the epithelial-mesenchymal transformation of pancreatic cancer. Moreover, neutrophils can also secrete elastase to degrade E-cadherin on pancreatic cancer cells, resulting in the enhanced migration and invasion of pancreatic cancer cells. In a mouse metastatic tumor model, NRF2 activity in P2RX1 negative neutrophils is elevated, leading to metabolic reprogramming during polarization. As a result, CD8+ T cells are inhibited, and tumor immune escape is mediated. NETs are upregulated in pancreatic cancer through a RAGE dependent and autophagy mediated pathway. NETs enhance the migration of hepatic stellate cells, activate cancer-associated fibroblasts, and promote hepatic metastasis of pancreatic cancer. Neutrophils are also involved in pancreatic cancer vascular endothelial cell integrity damage and promote metastasis of pancreatic cancer cells. CAF, cancer-associated fibroblasts; EMT, epithelial-mesenchymal transformation; PDAC, pancreatic ductal adenocarcinoma; PD-L1, programmed cell death-ligand 1; PSC, pancreatic stellate cell; IL, interleukin; EC, endothelial cell; NET, neutrophil extracellular trap.

Figure 3

Potential neutrophil-directed therapeutic targets in pancreatic cancer. Inhibition of chemokines and cytokines prevents neutrophil activation and recruitment, thereby reducing neutrophils in the TME. TGF-β inhibitors can reduce the tumor-promoting phenotype of neutrophils. In the TME, targeting neutrophil combined with immune checkpoint blockade can enhance the antitumor function in pancreatic cancer. NET inhibitors prevent cancer cell metastasis, circulating hypercoagulable states, and venous thrombosis formation. TME, tumor microenvironment; CAF, cancer-associated fibroblasts; PD-L1, programmed cell death-ligand 1; PD-1, programmed cell death 1; PMN-MDSC, polymorphonuclear-myeloid derived suppressor cell; NET, neutrophil extracellular trap.