Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice

Abstract

In this study, using single-cell RNA-seq, cell mass spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMNs) in cancer. We describe three populations of PMNs in tumor-bearing mice: classical PMNs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and activated PMN-MDSCs with potent immune suppressive activity. In spleens of mice, PMN-MDSCs gradually replaced PMNs during tumor progression. Activated PMN-MDSCs were found only in tumors, where they were present at the very early stages of the disease. These populations of PMNs in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMNs with characteristics of classical PMNs and PMN-MDSCs. The gene signature of tumor PMN-MDSCs was similar to that in mouse activated PMN-MDSCs and was closely associated with negative clinical outcome in cancer patients. Thus, we provide evidence that PMN-MDSCs are a distinct population of PMNs with unique features and potential for selective targeting opportunities.

Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer

“…Our results show that ASC can induce features of PMN-MDSC in mature neutrophils: low density, increased LOX-1 expression, and T-cell suppressor function. These results are consistent with the growing understanding of granulocyte diversity in the TME (50,51), and the notion of granulocyte subsets acquiring suppressor function through distinct pathways that include abnormal granulopoiesis (bona fide PMN-MDSC) and signaling pathways induced in the TME that render normal mature neutrophils suppressive.…”

Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies?

“…PMN-MDSCs are considered to represent a subset of neutrophils with immunosuppressive functions that are generated and accumulated during tumor development [35,139,140]. It was reported that TAN1 possess the characteristics of classical neutrophils, whereas TAN2 have features of PMN-MDSCs [14] (Table 1).…”

Frontiers in Pharmacology: Review Manuscript Targeting of the Neutrophil as an Adjunctive Strategy in Non-Small Cell Lung Cancer

“…However, recent evidence suggests that different PMN populations coexist in tumor bearing mice and cancer patients. In this context, three different PMN populations were found infiltrating the tumor: 30% corresponded to neutrophil-like PMNs, 16% classical PMN-MDSCs and 55% were activated PMN-MDSCs ( Veglia et al, 2021 ).…”

“…Genetically, the three sub-populations show distinct gene expression profiles, ranging from non-suppressive PMNs, to immature/suppressive PMN-MDSCs (both found mainly in the spleen of healthy or tumor-bearing mice), and high chemokine/ER stress responses in activated PMN-MDSCs, residing mainly in tumors ( Veglia et al, 2021 ). Interestingly, CD14 was shown to be a good marker of activated PMN-MDSCs in tumor-bearing mice, which was also associated with poor prognosis in cancer patients ( Veglia et al, 2021 ). Supporting these findings, Zilionis et al (2019) described similar neutrophil populations.…”

“…Notably, the ER stress response was also associated with pro-metastatic PMN populations, while activation of the XBP1/IRE1 pathway resulted in an increase of LOX1 gene expression, the signature of suppressive PMN-MDSCs ( Veglia et al, 2021 ).…”