Della Bella S, Gennaro M, Vaccari M, Ferraris C, Nicola S, Riva A, Clerici M, Greco M, Villa M L
Dipartimento di Scienze e Tecnologie Biomediche, Cattedra di Immunologia, Università degli Studi di Milano, LITA Segrate, via F.lli Cervi 93, Segrate (MI) 20090, Italy.
Br J Cancer. 2003 Oct 20;89(8):1463-72. doi: 10.1038/sj.bjc.6601243.
Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P<0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P=0.016), and had impaired production of IL-12 (P<0.001). These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumour-related immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs.
肿瘤至少有两种机制可改变树突状细胞（DC）的成熟和功能。第一种机制影响造血祖细胞分化为功能性DC的能力；第二种机制影响DC从CD14+单核细胞的分化，促进其早期但功能失调的成熟。本研究的目的是评估这些途径在乳腺癌患者体内的相关性。为此，将53例浸润性乳腺癌患者与68例健康对照进行了比较。为避免对DC进行分离或培养富集程序，直接通过流式细胞术对全血样本进行分析。评估了LPS刺激后表面抗原的表达和调节性细胞因子的细胞内积累。癌症患者的DC数量，尤其是髓样亚群的数量明显减少（P<0.001）。与对照组相比，患者的DC具有更成熟的表型（P=0.016），且IL-12的产生受损（P<0.001）。这些改变通过肿瘤手术切除得以逆转。为了研究一些肿瘤相关免疫活性可溶性因子的可能作用，我们测量了血管内皮生长因子、IL-10和精胺的血浆水平。发现精胺浓度与表达IL-12的DC百分比之间存在显著负相关。还获得证据表明，单核细胞来源的DC在体外暴露于精胺会促进其激活和成熟，并损害其功能。综上所述，我们的结果表明，上述两种机制可能在乳腺癌中同时起作用以影响DC分化，并且精胺可能是DC功能失调成熟的介质。
