Neutrophil Subtypes Play Different Roles During Cancer Development

Evidence presented in a recent paper suggests that the role of neutrophils in tumor biology may need to be reconsidered.

Neutrophils are the most abundant (40% to 75%) type of white blood cells in mammals and form an essential part of the innate immune system. These short-lived and highly motile phagocytes are formed from stem cells in the bone marrow. During the acute phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals in a process called chemotaxis. Neutrophil function in cancer has been a subject of controversy, as they have been shown to behave in both pro- and anti-tumor fashion.

Investigators at the Hebrew University of Jerusalem (Israel) working with mouse tumors and human blood samples identified a heterogeneous subset of low-density neutrophils (LDNs) that appeared transiently in self-resolving inflammation but accumulated continuously with cancer progression. LDNs displayed impaired neutrophil function and immunosuppressive properties, characteristics that were in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consisted of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that were derived from HDNs in a TGF-beta (transforming growth factor-beta) -dependent mechanism.

The LDN subpopulation consisted of at least two morphologically distinct neutrophil subsets that were regulated via discrete mechanisms. Furthermore, the mature, “normal,” HDNs were capable of switching to become LDNs in a TGF-beta-dependent fashion, a switch accompanied by loss of anti-tumor properties and the gain of immunosuppressive properties.

The overall circulating neutrophil phenotype switched from mostly anti-tumor early on to become more pro-tumor with tumor progression. Taken together, the data presented in this study revealed the existence of neutrophil subpopulations with conflicting functions and provided evidence for functional and physical neutrophil plasticity. These insights offered a mechanistic explanation to mitigate the controversy that surrounds neutrophil function in cancer and highlighted unexplored aspects of neutrophil biology.

Senior author Dr. Zvi Granot, professor of developmental biology and cancer research at the Hebrew University of Jerusalem, said, “The novel distinction between harmful and beneficial neutrophils opens up new diagnostic and therapeutic opportunities. We are currently evaluating the effects of boosting the helpful antitumor neutrophil population, while limiting the tumor-promoting neutrophil population, on progression of the disease. If successful, this therapeutic strategy may take us closer to developing effective new therapies for cancer.”

The study was published in the January 22, 2015, online edition of the journal Cell Reports.

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