Neutrophils in the tumor microenvironment – when a company becomes a crowd
Zvi G. Fridlender, Zvi Granot
Abstract
Traditionally, neutrophils are perceived as terminally differentiated cells with defined functions and limited plasticity. It is commonly believed that circulating, marginating and tissue-infiltrating neutrophils belong to the same homogeneous population and are capable of switching between these locations. Neutrophil research has stagnated since the early 1980s, maintaining a narrow and simplistic view of their capabilities. Over the past two decades, substantial advances in our understanding of neutrophils have revealed them to be a plastic and diverse population of cells [ 1 , 2 ]. Several seminal studies have challenged the conventional perception of neutrophils, particularly in the context of cancer, where their role has been hotly debated. These studies demonstrated that neutrophils can exert either pro- or antitumor effects [ 3 ]. This controversy was ultimately resolved with the recognition that neutrophils constitute a heterogeneous population, exemplified by the discovery of two distinct tumor-associated neutrophil subsets, N1 and N2 with antitumor and protumor properties, respectively [ 4 ]. Moreover, the phenotype of neutrophils is influenced by molecular cues within the tumor microenvironment, contributing to a broader “immunosuppressive switch” that characterizes tumor progression [ 5 ]. In addition to these findings, a unique subset of neutrophils with lower density, termed low-density neutrophils (LDNs), was identified in cancer. LDNs differ from normal-density neutrophils (NDNs) and encompass at least two subpopulations: mature and immature LDNs. Furthermore, studies have shown that neutrophils can transition between the NDN and LDN states, underscoring their remarkable plasticity [ 2 ]. Importantly, while the plasticity of neutrophils initially gained recognition in the context of cancer, its importance extends to various clinical scenarios including chronic inflammation and infectious diseases [ 1 ]. Here we highlight the broad relevance and importance of understanding the diverse nature of neutrophils beyond their traditional roles.