Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.

The importance of tumor associated neutrophils (TANs) in cancer development is in the meantime well established. Numerous of clinical data document the adverse prognostic effects of neutrophil infiltration in solid tumors. However, certain tumor therapies need functional neutrophils to be effective, suggesting altered neutrophil polarization associated with different outcomes for cancer patients. Therefore, modulation of neutrophilic phenotypes represents a potent therapeutic option, but factors mediating neutrophil polarization are still poorly defined. In this manuscript we provide evidence that type I IFNs alter neutrophilic phenotype into anti‐tumor, both in mice and human. In the absence of IFN‐β, pro‐tumor properties, such as reduced tumor cytotoxicity with low neutrophil extracellular traps (NETs) expression, low ICAM1 and TNF‐α expression, dominated neutrophil phenotypes in primary lesion and premetastatic lung. Interestingly, such neutrophils have significantly prolonged life‐span. Notably, interferon therapy in mice altered TAN polarization towards anti‐tumor N1. Similar changes in neutrophil activation could be observed in melanoma patients undergoing type I IFN therapy. Altogether, these data highlight the therapeutic potential of interferons, suggesting optimization of its clinical use as potent anti‐tumor agent.

In tumor-bearing mice, immunosuppressive granulocytic and monocytic MDSC have been identified. The identity and function of MDSC in cancer patients are less clear and need further characterization. We analyzed the peripheral blood of 103 patients with HNC, lung cancer, or cancers of bladder and ureter. Based on sedimentation properties in density gradients, a subset of LD-PMN was identified and analyzed. LD-PMN were expanded in the peripheral blood of cancer patients, suppressed proliferation, and IFN-γ production of polyclonally stimulated T cells and thus, qualify as human MDSC. Immunophenotyping and morphological analysis revealed the accumulation of immature PMN in the MDSC fraction. Neutrophilic MDSC showed altered surface marker expression, prolonged survival, and impaired effector functions when compared with conventional, mature PMN of regular density. MDSC displayed markedly reduced chemotaxis toward tumor-conditioned medium and lacked expression of chemokine receptors CXCR1 and CXCR2, which are normally required for PMN extravasation from the bloodstream and subsequent tissue infiltration. Collectively, our data suggest the accumulation and persistence of long-lived, immature granulocytic MDSC with T cell-suppressive function and impaired migratory properties in the peripheral blood of cancer patients.