Data_Sheet_1_IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients.pdf

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.

本研究旨在筛选可改变晚期黑色素瘤患者髓系来源抑制性细胞（MDSCs）频率，并与临床结局相关的肿瘤分泌因子。本研究聚焦于参与MDSCs扩增与动员的诸多因子中的数种，通过检测55例IV期黑色素瘤患者与22例健康对照者的循环13种细胞因子及生长因子浓度，筛选出了相关因子。基于上述检测结果，我们提出假设：黑色素瘤细胞分泌的白细胞介素6（IL-6）与白细胞介素8（IL-8）可参与MDSCs的扩增与募集，且二者联合可预测黑色素瘤患者的总生存期。随后，我们对比了黑色素瘤组织中IL-6、IL-8的表达水平与对应血浆浓度及循环MDSCs频率，并分析这些指标与临床结局的相关性。与指标浓度较低的患者相比，血浆IL-6浓度升高者（占比40%）、IL-8浓度升高者（占比63%），或二者均升高者（占比35%）的中位总生存期更短。外周血IL-6、IL-8浓度较低且肿瘤组织中二者表达量较低的患者，其循环MDSCs频率更低；而循环MDSCs频率较低的患者总生存期更优。既往研究已证实IL-6可扩增MDSCs，本研究则证实MDSCs可被IL-8趋化募集。多因素分析显示，同时存在IL-6与IL-8高表达（风险比HR=3.059）以及MDSCs高频率（HR=4.265）的受试者死亡风险升高。综合上述结果可见，IL-6与IL-8在黑色素瘤患者中发挥重要作用：IL-6可扩增外周血MDSCs，而IL-8则将这些强免疫抑制性细胞募集至肿瘤微环境中。本研究进一步支持了以IL-6、IL-8及MDSCs为靶点开发潜在治疗手段，以改善黑色素瘤治疗方案的可行性。