Brave little world - Spheroids as an in vitro model to study tumor-immune-cell interactions
Brave little world - Spheroids as an in vitro model to study tumor-immune-cell interactions
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DOI：
10.4161/cc.5.7.2624
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发表时间：
2006-04-01
期刊：
影响因子：
4.3
通讯作者：
Kreutz, Marina
中科院分区：
文献类型：
--
作者：
Gottfried, Eva;Kunz-Schughart, Leoni A.;Kreutz, Marina
多细胞肿瘤球体（MCTS）是一种成熟的三维体外模型系统，反映了肿瘤微区和无血管微转移部位的病理生理学体内情况。由于单核细胞和其他免疫细胞浸润到不同来源的MCTS，这种球状体共培养物是一个有价值的，仍然低估的工具，系统地研究肿瘤和免疫细胞之间的异源相互作用。本文简要概述了已发表的关于MCTS中肿瘤-免疫细胞相互作用的工作，并总结了肿瘤环境中免疫抑制的机制，重点是骨髓细胞。使用共培养模型，我们最近证明，肿瘤来源的乳酸是一种有效的调节人单核细胞的乳酸抑制单核细胞（MO）分化为树突状细胞（DC），也受损的抗原呈递。我们在此表明，MCTS中各种肿瘤细胞分泌乳酸的能力相差高达10倍，这表明这种能力取决于肿瘤细胞类型。进一步证明，乳酸干扰MO迁移到MCTS中，因为可以通过阻断乳酸产生来增加渗透。因此，我们讨论了在许多肿瘤和肿瘤微区中积累的乳酸作为肿瘤环境中MO/DC的有效免疫抑制剂，并得出结论，这些数据与DC过继免疫治疗方案高度相关。
Multicellular tumor spheroids (MCTS) are a well-established 3-D in vitro model system that reflects the pathophysiological in vivo situation in tumor microregions and of avascular micrometastatic sites. Because monocytes and other immune cells infiltrate into MCTS of different origin, such spheroid cocultures are a valuable, still underestimated tool to systematically study heterologous interactions between tumor and immune cells. The present article gives a brief overview on work that has been published on tumor-immune cell interactions in MCTS and also summarizes mechanisms of immune suppression in the tumor milieu focussing on myeloid cells. Using the coculture model, we recently demonstrated that tumor-derived lactic acid is a potent modulator of human monocyte as lactic acid inhibited the differentiation of monocytes (MO) into dendritic cells (DC) and also impaired antigen presentation. We show herein, that the capacity of various tumor cells in MCTS to secrete lactic acid differs up to tenfold, suggesting that this capacity is dependent on the tumor cell type. It is further demonstrated that lactic acid disturbs the migration of MO into MCTS as infiltration could be increased by blocking lactic acid production. We therefore discuss lactic acid which accumulates in many tumors and tumor microregions as a potent immune suppressor for MO/DC in the tumor milieu and conclude that these data are highly relevant for adoptive immunotherapy protocols with DC.