Unique pattern of neutrophil migration and function during tumor progression

Abstract

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancers exhibited much more spontaneous migration to tissues. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and much more production of ATP. Their enhanced spontaneous migration was mediated by the binding of ATP to purinergic receptors. In ectopic tumor models and the late stages of cancers, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed in neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils’ contribution to early tumor dissemination.

Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis

“…39 Future studies are needed to understand the mechanisms behind LDN accumulation in the bloodstream and whether these cells have an impact on disease progression and severity. 49,50 One of the current challenges in the field of myeloid cells in cancer is the phenotypic characterization and cancer-driven modulations these cells in general, and neutrophils in particular, undergo in cancer. 51,52 Since the first documentations of the presence of LDN within the classical "PBMC fraction" following density gradient, [18][19][20] few specific markers have been suggested to characterize cancer-related neutrophils, including the distinction between LDN and HDN, as well as mature vs immature neutrophils.…”

High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy

“…In a recent study, Patel et al proposed a potential mechanism to explain these seemingly incongruent findings by identifying distinct subpopulations of neutrophils in mouse models and patients with cancer. Although a particularly immunosuppressive neutrophil phenotype is enriched in animal models of metastatic disease, early in the development of cancer, neutrophils appear to have increased migratory activity but lack immunosuppressive function . The mechanism driving this phenomenon remains to be fully defined, but this increased migratory activity outside of the bone marrow may explain the neutrophilia seen in many patients with cancer and help establish the immunosuppressive population of neutrophils that ultimately promotes tumor growth and underlies the poor prognosis associated with a high NLR.…”

Cell autonomous versus systemic Akt isoform deletions uncovered new roles for Akt1 and Akt2 in breast cancer

“…The pro-metastatic role of neutrophils was also recognized in human cancer patients, and a high NLR is associated with a poor prognosis 14 . The neutrophils derived from tumor-bearing mice or from cancer patients are distinct from normal neutrophils, as tumor-associated neutrophils lack immunosuppressive activity and have a higher migration capacity 26 . Cancer cells promote the survival and mobilization of neutrophils by secreting G-CSF 14, 27 .…”