Uncovering common transcriptional features shared by mature peripheral blood PMN-MDSCs and tumor-infiltrating neutrophils in humans

Human polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) consist of circulating low-density neutrophils (LDNs) characterized by the ability to inhibit T-cell responses. In previous studies, we demonstrated that the mature fraction of PMN-MDSCs (i.e. mPMN-MDSCs) exerts more potent immunosuppressive functions than its immature counterpart. More recently, we defined a specific gene signature of mPMN-MDSCs from cancer patients and G-CSF-treated donors (GDs) by bulk RNA sequencing (RNA-seq) experiments. In this study, by performing single-cell RNA-seq (scRNA-seq) experiments of circulating mPMN-MDSCs from non-small cell lung cancer (NSCLC) patients, we identified a major scRNA-seq cell cluster (arbitrarily named NSCLC c6) specifically displaying immunosuppressive and protumor transcriptomic features. Then, by analyzing publicly available scRNA-seq datasets from human tumor-associated neutrophils (TANs), we uncovered three TAN clusters (arbitrarily named TAN c6-c8) that were found to share with NSCLC c6 several common genes and transcription factor (TF) regulons associated with response to hypoxia, positive regulation of angiogenesis, and metabolic reprogramming. Furthermore, by performing scRNA-seq experiments of GD mPMN-MDSCs, we uncovered four scRNA-seq cell clusters (arbitrarily named GD c4-c7) that were enriched for the same genes and pathways characterizing NSCLC c6 and TAN c6-c8 cells. Altogether, these data uncover that human circulating mPMN-MDSCs and TANs from different cancer types share scRNA-seq cell clusters with transcriptomic similarities, supporting the notion that they might be strictly related.