A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma

Abstract

Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3(-), CD19(-), CD56(-)), HLA-DR(-/low), CD11b(+) and CD33(+). Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) < 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI.

Increased Levels of Circulating and Tumor-Infiltrating Granulocytic Myeloid Cells in Colorectal Cancer Patients

“…However, there were no differences in GMCs levels between patients with different tumor stages. These results are in agreement with previous studies in CRC and cutaneous melanoma, which have also shown higher levels of MDSCs in metastatic cancers compared with control group (10, 26). There are studies, however, which reported significant differences in levels of myeloid cells between HDs and patients with low stage cancers, and between patients with different cancer stages (25, 28); this discrepancy could be due to the number of patients and type of cancer investigated.…”

“…Additionally, we report that these expanded cells are granulocytic in nature. Studies on other cancers including cutaneous melanoma also reported the accumulation of circulating granulocytic MDSC like cells in patients compared to HDs (10, 32). Zhang et al, however, reported the expansion of IMCs lacking CD14 and CD15 in CRC (26).…”

“…We used freshly drawn whole blood for analysis because various studies emphasized on the importance of sample handling and processing when monitoring levels of myeloid cells in circulation (10, 28, 30, 31). Florcken et al did not find any differences in the expression levels of MDSC when analyzed in whole blood or PBMCs (31).…”

“…However, Mandruzzato et al suggested to monitor MDSC levels in whole blood instead of Ficoll-purified mononuclear cells as some MDSC subsets might not be detected if only PBMCs were examined (30). Fresh blood is preferred to prevent possible loss of GMCs and attenuation of cell surface markers due to Ficoll gradient separation (10). …”

“…Human MDSCs are broadly classified into monocytic (M) and granulocytic (G) or polymorphonuclear (PMN) subset based on the expression of CD14 and CD15 markers (8). Monocytic MDSCs (M-MDSCs) are mostly CD33 + CD11b + CD14 + HLA-DR −/low , whereas granulocytic MDSCs (G-MDSCs) are CD33 + CD11b + HLA-DR −/low CD14 − CD15 + (9, 10). A third population of MDSCs has also been described as immature or early stage MDSCs, lacking CD14, CD15, and HLA-DR (11).…”