Cancer-related circulating and tumor-associated neutrophils – subtypes, sources and function

In recent years, the role of neutrophils in cancer biology has been a matter of increasing interest. Many patients with advanced cancer show high levels of neutrophilia, tumor neutrophils are connected to dismal prognosis, and the neutrophil-to-lymphocyte ratio has been introduced as a significant prognostic factor for survival in many types of cancer. Neutrophils constitute an important portion of the infiltrating immune cells in the tumor microenvironment, but controversy has long surrounded the function of these cells in the context of cancer. Multiple evidences have shown that neutrophils recruited to the tumor can acquire either protumor or antitumor function. These findings have led to the identification of multiple and heterogeneous neutrophil subsets in the tumor and circulation. In addition, tumor-associated neutrophils (TANs) were shown to demonstrate functional plasticity, driven by multiple factors present in the tumor microenvironment. In this review, we examine the current knowledge on cancer-related circulating neutrophils, their source and the function of the different subtypes, both mature and immature. We then discuss the pro vs antitumor nature of TANs in cancer, their functional plasticity and the mechanisms that regulate neutrophil recruitment and polarization. Although the vast majority of the knowledge on neutrophils in cancer comes from murine studies, recent work has been done on human cancer-related neutrophils. In the final paragraphs, we expand on the current knowledge regarding the role of neutrophils in human cancer and examine the question whether cancer-related neutrophils (circulating or intratumoral) could be a new possible target for cancer immunotherapy.