Tumor-derived lactic acid modulates dendritic cell activation and antigen expression
Tumor-derived lactic acid modulates dendritic cell activation and antigen expression
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DOI：
10.1182/blood-2005-05-1795
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Kreutz, M
中科院分区：
文献类型：
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作者：
Gottfried, E;Kunz-Schughart, LA;Kreutz, M
肿瘤环境可影响树突状细胞（DC）分化。我们在三维肿瘤模型中分析了DC分化，并提出了肿瘤环境调节DC的新机制。单核细胞在IL-4和GM-CSF的存在下，在不同肿瘤细胞系产生的多细胞肿瘤球体（MCTSs）中培养。单核细胞侵入MCTSs并分化为肿瘤相关树突状细胞（TADCs）。与培养条件无关的tdac（未成熟/成熟dc，朗格汉斯细胞）上抗原表达发生改变，IL-12分泌减少。MCTSs上清液可以部分转移抑制作用。来自尿路上皮癌细胞系的条件培养基含有高水平的M-CSF和IL-6，这两种细胞因子都可以调节DC分化。相比之下，黑色素瘤和前列腺癌MCTS共培养产生少量M-CSF和IL-6，但乳酸水平较高。事实上，在体外DC分化过程中添加乳酸诱导的表型与黑色素瘤和前列腺癌MCTSs中产生的TADCs相似。阻断黑色素瘤MCTS共培养的乳酸产生使tdac表型恢复正常。因此，我们得出结论，肿瘤来源的乳酸是调节肿瘤环境中DC表型的重要因素，可能对肿瘤逃逸机制起关键作用。
The tumor milieu can influence dendritic cell (DC) differentiation. We analyzed DC differentiation in a 3-dimensional tumor model and propose a new mechanism of DC modulation by the tumor environment. Monocytes were cultured in the presence of IL-4 and GM-CSF within multicellular tumor spheroids (MCTSs) generated from different tumor cell lines. Monocytes invaded the MCTSs and differentiated into tumor-associated dendritic cells (TADCs). The antigen expression was altered on TADCs independent of the culture conditions (immature/mature DCs, Langerhans cells) and IL-12 secretion was reduced. Supernatants of MCTSs could partially transfer the suppressive effect. Conditioned media from urothelial carcinoma cell lines contained high levels of M-CSF and IL-6, both cytokines known to modulate DC differentiation. In contrast, melanoma and prostate carcinoma MCTS cocultures produced little M-CSF and IL-6, but high levels of lactic acid. Indeed, addition of lactic acid during DC differentiation in vitro induced a phenotype comparable with TADCs generated within melanoma and prostate carcinoma MCTSs. Blocking of lactic acid production in melanoma MCTS cocultures reverted the TADC phenotype to normal. We therefore conclude that tumor-derived lactic acid is an important factor modulating the DC phenotype in the tumor environment, which may critically contribute to tumor escape mechanisms.