Untreated stage IV melanoma patients exhibit abnormal monocyte phenotypes and decreased functional capacity.
Untreated stage IV melanoma patients exhibit abnormal monocyte phenotypes and decreased functional capacity.
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DOI：
10.1158/2326-6066.cir-13-0094
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发表时间：
2014-03
影响因子：
10.1
通讯作者：
Markovic SN
中科院分区：
文献类型：
--
作者：
Chavan R;Salvador D;Gustafson MP;Dietz AB;Nevala W;Markovic SN
单核细胞可能通过介导肿瘤诱导的免疫抑制在一定程度上促进肿瘤的进展。未经治疗的晚期黑色素瘤患者单核细胞数量和功能的改变尚不完全清楚。为了确定这些变化的特征，我们比较了未经治疗的、新诊断的IV期黑色素瘤患者(n=18)与健康志愿者外周血单核细胞和其他髓系细胞的频率、表型和功能能力。IV期未经治疗的黑色素瘤患者的单核细胞百分比显著下降(p<；0.0001)，其中包括CD14+CD16−经典单核细胞池的百分比下降(p=0.006)。尽管黑色素瘤患者CD14+HLADRlow/−单核细胞群与健康志愿者无显著差异，但CD14+CD16+中间体(p<；0.0001)和CD14lowCD16+非经典型单核细胞群(p=0.001)的HLADR水平显著低于健康志愿者。黑色素瘤患者单核细胞表面CD86(p=0.0006)和TNFRⅡ(p=0.0001)表达减少，组织因子和PD-L1表达增加(p=0.003)。此外，在Toll样受体3激动剂(TLR3)刺激下，这些单核细胞上调CD80表达和细胞因子产生的能力降低。未经治疗的IV期黑色素瘤患者外周血树突状细胞亚群减少。我们的研究表明，未经治疗的晚期黑色素瘤患者除了表现出可能对患者免疫功能产生负面影响的表型和功能缺陷外，还会出现单核细胞减少症。这些发现为研究单核细胞群体在黑色素瘤发展中的作用开辟了新的途径。
Monocytes may contribute to tumor progression in part by mediating tumor-induced immunosuppression. Alterations to the monocyte populations and functions in untreated late stage melanoma patients are not fully understood. To characterize these alterations, we compared the frequency, phenotype, and functional capacity of peripheral blood monocytes and other myeloid cells in untreated, newly diagnosed stage IV melanoma patients (n= 18) to those in healthy volunteers. Stage IV untreated melanoma patients exhibited a sizeable decrease in the percentage of monocytes (p<0.0001) that included a drop in the percentage of CD14+CD16− classical monocytes pool (p=0.006). Although there was not a significant difference in the CD14+HLA-DRlow/− monocyte population between the melanoma patients and the healthy volunteers, the HLA-DR levels were considerably lower in the patients’ CD14+CD16+ intermediate (p<0.0001) and CD14lowCD16+ non-classical monocytes populations (p=0.001). Decreased surface expression of CD86 (p=0.0006) and TNFRII (p=0.0001), and increased expression of tissue factor and PD-L1 (p=0.003) were identified on monocytes from melanoma patients. Furthermore, these monocytes had decreased ability to up-regulate CD80 expression and cytokine production following stimulation with agonist of toll-like receptor 3 (TLR3). Peripheral blood dendritic cell subsets were decreased in untreated stage IV melanoma patients. Our study demonstrates that untreated late stage melanoma patients exhibit monocytopenia in addition to phenotypic and functional deficiencies that may negatively affect the patient’s immune function. These findings open new avenues into examining the role of monocyte populations in melanoma development.