Phenotypic Diversity and Plasticity in Circulating Neutrophil Subpopulations in Cancer

• Low-density neutrophils are preferentially propagated in cancer
• LDNs consist of both mature and immature neutrophils
• The mature subtype of LDNs acquires suppressive functions
• Neutrophil contribution switches from anti- to protumor with tumor progression

SummaryControversy 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.

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