Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology

Abstract

Accumulating evidence indicates that myeloid cells are critically involved in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages, the significance of granulocytes in cancer has only recently begun to emerge. A number of studies found increased numbers of neutrophil granulocytes and granulocytic myeloid-derived suppressor cells (GrMDSCs) both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Most importantly, granulocytes have been linked to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting effects. In this review, we will address in detail the following major topics: (1) neutrophils and GrMDSCs in the peripheral blood of cancer patients-phenotype and functional changes; (2) neutrophils and GrMDSCs in the tumor tissue-potential mechanisms of tumor progression and (3) relevance of neutrophils and GrMDSCs for the clinical outcome of cancer patients. Furthermore, we will discuss the advantages and disadvantages of the current strategies used for identification and monitoring of human MDSCs. We propose a six-color immunophenotyping protocol that discriminates between monocytic MDSCs (MoMDSCs), two subsets of GrMDSCs and two subsets of immature myeloid cells in human cancer patients, thus, allowing for an improved characterization and understanding of these multifaceted cells.

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

“…30,31 Nevertheless, neutrophils represent an independent prognostic marker in a broad variety of neoplasias. For instance, a high number of intratumoral neutrophils in localized 32 as well as metastatic 32 renal cell carcinoma, correlates with a negative prognosis.…”

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

“…When viewed in combination, these markers were suggestive of a granulocytic/neutrophilic MDSC subtype (PMN-MDSCs). 18,29 Percentages of monocytic MDSCs in peripheral blood were substantially lower (monocytic MDSCs mean 0.12% before ECP) compared with PMN-MDSCs (mean 6% before ECP) in our patient cohorts and did not change significantly upon ECP treatment (Supplementary Figure 2). We therefore systematically followed up on the observation that ECP Table 1.…”

“…Several factors have been involved into the generation and functionality of MDSCs, particularly arginase, Signal Transducer and Activator of Transcription 3 (STAT3), indoleamine 2,3-dioxygenase (IDO), reactive oxygen species and others. 18,19 As previous studies found that ECP enhances arginase I mRNA expression and enzyme activity in GvHD patients, 31 we focused on this pathway in our study. Our analyses demonstrated that ECP treatment increased arginase I activity both extracellularly in serum and intracellularly in the PMN-MDSC-containing PBMC fraction in GvHD patients, with PMN-MDSCs showing tendentially higher arginase I activity compared with autologous PBMCs (Figure 2c and Supplementary Figure 7).…”

“…In combination, these analyses showed that the neutrophilic myeloid cell population increased by ECP treatment indeed controls T-cell responses and can therefore be termed as a bona fide MDSC subpopulation according to the current view. 18,30 Given the induction of functional PMN-MDSCs, we next asked which mechanism is employed by these cells to downregulate T-cell responses. Several factors have been involved into the generation and functionality of MDSCs, particularly arginase, Signal Transducer and Activator of Transcription 3 (STAT3), indoleamine 2,3-dioxygenase (IDO), reactive oxygen species and others.…”

“…17 Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell population characterized by their capacity to potently suppress T-cell proliferation and T-cell cytokine responses. 18,19 Although MDSCs have been initially reported to have a role in cancer, an emerging body of evidence suggests that MDSCs are induced in a broad variety of chronic inflammatory disease conditions as an intrinsic anti-inflammatory mechanism induced to dampen excessive T-cell activities. 20 Functionally, MDSCs are comparable to Tregs, but can be characterized and isolated based on surface marker expression profiles.…”