Human immunosuppressive neutrophils: recent answers to old and new questions

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) represent the most investigated type of "immunosuppressive" neutrophils in humans. However, a detailed understanding of human PMN-MDSCs has been hindered for years by limited knowledge of their specific markers for sorting and purification, as well as by their very low numbers in patient circulation. Recently, the use of advanced technologies has shown that human PMN-MDSCs are generated during emergency granulopoiesis and comprise a heterogeneous population of both immature and mature neutrophils. It has also been shown that human mature PMN-MDSCs (mPMN-MDSCs) perform immunosuppressive functions through transcriptional reprogramming during maturation. Furthermore, single-cell RNA sequencing experiments have shown that human mPMN-MDSCs and tumor-associated neutrophils (TANs) share transcriptomic similarities, therefore uncovering a potential relationship between them. In this Perspective, we discuss: i) how our knowledge on human PMN-MDSCs has advanced; ii) the criteria for discriminating human PMN-MDSCs from normal neutrophils or other immunosuppressive neutrophil populations; iii) recent findings revealing that human mPMN-MDSCs exhibit transcriptomic features suggestive of functions beyond immunosuppression.