Single cell sequencing of neutrophils demonstrates phenotypic heterogeneity and functional plasticity in health, disease, and cancer

A vital constituent of innate immunity, neutrophils had previously been considered functionally rigid with a fixed, defined role in host pathogen response, in part due to their fleeting lifespan. However, that consensus opinion has changed with evidence of functional neutrophil plasticity in a range of diseases including cancer. Typically difficult to sequence due to their low level of transcriptomic activity, advances in single cell RNA sequencing has allowed for closer examination of the neutrophil transcriptome in humans and mouse models and their interaction with other immune system constituents, both in health and disease, allowing for description of neutrophil phenotypes beyond previous descriptions reliant upon microscopic appearance, surface marker expression, and function. Transcriptomic analysis shows that neutrophils develop and mature along a fixed trajectory, but their transcriptome varies based on maturity, the insult that has provoked release from the bone marrow, and the tissue to which they are recruited. Thus neutrophil heterogeneity increases with maturity, with immature neutrophils being more transcriptomically rigid. Here, we review work done in neutrophil single cell RNA sequencing in mice and humans in health and a range of disease states including coronavirus disease 2019 (COVID-19) infection, and solid cancers to provide a template for understanding neutrophil biology in context.