Neutrophils as a Therapeutic Target in Cancer

Abstract

Neutrophils are the most abundant population of white blood cells in the human circulation. They are terminally differentiated myeloid cells which were traditionally associated with fighting infections and inflammatory processes. While this perception of neutrophils is still widely prevalent, in the past decade it has become clear that neutrophils also play a critical role in tumor growth and progression. The unique tumor microenvironment, consisting of the non-malignant stroma that surrounds tumor cells, is shaped by numerous cues emanating from both tumor cells and stromal cells which support the growing tumor. Various immune cells, including neutrophils, make up a significant proportion of the tumor stroma. Immune cells exist for the protection of the host against various threats including the detection and elimination of cancerous cells. However, in the context of cancer immune cells are often coerced into a tumor supportive phenotype. This is also the case for neutrophils, which are often described to possess tumor promoting properties and to associate with poorer prognosis. The fact that neutrophils may contribute to tumor growth and progression suggests they may be targets for anti-cancer therapies. This review discusses the various functions neutrophils may play in cancer and the possibility of targeting these functions as a novel mode of immunotherapy.

Keywords: cancer; metastasis; neutrophils; therapy; tumor microenvironment.

Figure 1

Neutrophil functions in cancer and potential therapeutic targets. Neutrophils play various and conflicting roles in cancer. Tumor promoting functions (red arrows) and anti tumor functions (blue arrows) are executed by specific molecular mediators. Tumor promoting propeties: Neutrophils promote tumor cell dissemination by degradation of the ECM at the primary and premetastatic sites and promote tumor cell seeding by deploying NETs. Promotion of angiogenesis is mediated by secretion of VEGF and HGF and the release of angiogenic factors from the ECM by neutrophil derived MMP9. Neutrophil mediate immune supprssion via the secretion of ROS and Arginase 1 to limit T cell dependent anti-tumor immunty. Anti-tumor properties: Neutrophils limit tumor growth and metastatic progression by eliminating tumor cells either directly or via antibody dependent mechanisms. Neutrophils can stimulate anti-tumor adaptive immune by acting as antigen presenting cells, secretion of TNFα, secretion of Elastase and secretion of Cathepsin G (Cath G).