Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that are derived from HDNs in a TGF-β-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.

Neutrophils play an established role in host defense and in killing invading microorganisms. Although neutrophils are traditionally considered in the context of their antibacterial functions, it is becoming increasingly clear that tumor-associated neutrophils (TAN) play a major role in cancer biology. Neutrophils make up a significant portion of the inflammatory cell infiltrate in many models of cancer. Like all other leukocytes, they move into tissues under the influence of specific chemokines, cytokines and cell adhesion molecules. The tumor microenvironment has been shown to be responsible for their recruitment in cancer. We have found that TAN are a distinct population of neutrophils, differing markedly in their transcriptomic profile from both naive neutrophils and the granulocytic fraction of myeloid-derived suppressor cells. Studies have demonstrated specific examples of tumor-mediated signals (such as transforming growth factor-β) that induce the formation of a pro-tumorigenic (N2) phenotype capable of supporting tumor growth and suppressing the antitumor immune response. However, there are also studies showing that TAN can also have an antitumorigenic (N1) phenotype. Herein, we explore the literature on the different mechanisms of TAN recruitment to tumors, the unique characteristics of TAN and what shapes their pro- and/or antitumor effects.

Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer.