Abstract
We sought to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We focused our study on several of the many factors involved in the expansion and mobilization of MDSCs. These were identified by measuring circulating concentrations of 13 cytokines and growth factors in stage IV melanoma patients (n = 55) and healthy controls (n = 22). Based on these results, we hypothesized that IL-6 and IL-8 produced by melanoma tumor cells participate in the expansion and recruitment of MDSCs and together would be predictive of overall survival in melanoma patients. We then compared the expression of IL-6 and IL-8 in melanoma tumors to the corresponding plasma concentrations and the frequency of circulating MDSCs. These measures were correlated with clinical outcomes. Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%), or both (35%) had worse median overall survival compared to patients with low concentrations. Patients with low peripheral concentrations and low tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs, and patients with low frequencies of MDSCs had better overall survival. We have previously shown that IL-6 is capable of expanding MDSCs, and here we show that MDSCs are chemoattracted to IL-8. Multivariate analysis demonstrated an increased risk of death for subjects with both high IL-6 and IL-8 (HR 3.059) and high MDSCs (HR 4.265). Together these results indicate an important role for IL-6 and IL-8 in melanoma patients in which IL-6 potentially expands peripheral MDSCs and IL-8 recruits these highly immunosuppressive cells to the tumor microenvironment. This study provides further support for identifying potential therapeutics targeting IL-6, IL-8, and MDSCs to improve melanoma treatments.
Highlights
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature, immunosuppressive myeloid lineage cells that increase in frequency in tumor-bearing hosts [1,2,3,4]
To determine whether peripheral cytokines are increased in patients diagnosed with advanced melanoma, we began by identifying cytokines with increased concentrations in the plasma of stage IV melanoma patients compared to healthy donors at the time of study enrollment
Concentrations of the cytokines IL1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), macrophage inhibitory protein-1A (MIP-1A), MIP-1B, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed (Figure 1A). We found that both IL-6 (p = 0.0151) and IL-8 (p = 0.0078) were increased in stage IV patients compared to healthy donors, and that IL-8 was elevated in stage IV compared to stage I patients (Figures 1A,B, p = 0.0257)
Summary
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature, immunosuppressive myeloid lineage cells that increase in frequency in tumor-bearing hosts [1,2,3,4]. Accumulation of MDSCs, via recruitment or expansion within the periphery or tumor microenvironment, presents a significant obstacle to an effective anti-tumor immune response [1, 3,4,5]. MDSCs inhibit the ability of other immune cells to kill tumor cells by producing soluble factors such as interleukin (IL)-10, transforming growth factor-β (TGFβ), arginase 1 (Arg1), and reactive oxygen species (ROS) as well as by direct cell:cell interactions [3, 4]. Melanoma patients with high frequencies of MDSCs have decreased overall survival (OS), progression-free survival, and increased risk of death [1, 3, 4]. High frequencies of MDSCs appear to limit the efficacy of immunotherapies such as anti-CTLA4 (ipilimumab) and anti-PD1 (pembrolizumab and nivolumab) [6]
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