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

Abstract

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.

Neutrophil Diversity in Health and Disease

“…Many researchers in the field regard PMN-MDSCs as being a distinct population of cells. However, many others believe that PMN-MDSCs are not a unique separate cell population but are instead a subgroup of neutrophils with suppressive activity [109]. Moreover, we do not currently see a phenotypic path to distinguishing N2 TANs from PMN-MDSCs in tumors.…”

“…However, there is significant phenotypic and functional overlap between PMN-MDSCs and neutrophils, making it hard to clearly separate the two [57,66,109]. Many researchers in the field regard PMN-MDSCs as being a distinct population of cells.…”

“…For instance, mouse neutrophils are defined as CD11b +-GR1 + Ly6G + cells [124], and mouse PMN-MDSCs are also defined as CD11b + GR1 + Ly6G + , although they have suppressive activity [124]. In humans, mature neutrophils are defined as CD15 + CD66b + CD16 + CD14 − [66,109], and human PMN-MDSCs are defined by a more complex phenotypic panel containing at least six markers, namely CD15 + CD66b + CD16 +/ − CD14 − CD11b +/− CD33 + HLA-DR − [57,66,134]; however, this could also describe regular neutrophils. Indeed, the suggested term 'PMN-MDSC-like' to describe cells with surface markers of 'PMN-MDSCs but no suppressive activity' [124], has not been accepted in the field.…”

“…[57,66,124]. However, in some studies LDNs have been defined as PMN-MDSCs without testing their inhibitory actions on T cell functions, or have not even been reported to be suppressive [54,109]. Furthermore, whether and to what degree circulating normal-density neutrophils (NDNs) from cancer patients also display suppressive properties remains poorly defined.…”

“…Humans Multiple and heterogeneous neutrophil populations displaying either pro-or antitumor functions have been identified within the circulation and tumor tissues of cancer patients, as well of tumorbearing mice [109]. For instance, LDNs/PMN-MDSCs (Boxes 1 and 2, and Figure 4) have been consistently found in the blood of a variety of cancer patients, such as non-small cell lung cancer (NSCLC), head and neck cancer (HNC), hepatocellular carcinoma, colorectal cancer, and more, and the frequency of these cells often correlates with disease severity and/or responsiveness to treatment [57,66,109].…”