德国Regensburg大学：肿瘤自卫的武器：乳酸，保护自己、抵御免疫细胞的攻击

Inhibitory effect of tumor cell-derived lactic acid on human T cells

　

肿瘤细胞其中的一个显著特征是大量摄取葡萄糖进行乳酸发酵（进行有氧糖酵解），产出大量的乳酸。

这个由德国Regensburg大学（University of Regensburg）进行的实验，显示了血清乳酸水平和病人的肿瘤负担的正相关性以及在体外乳酸如何影响免疫细胞。乳酸对细胞毒性T淋巴细胞（CTLs）的增殖和细胞因子的产生的抑制率达90%，并且导致其细胞毒性活力下降50%。这些受乳酸抑制的细胞毒性T淋巴细胞的功能在转移到不含乳酸的环境24小时内恢复正常。渗透入产生乳酸的多细胞肿瘤球体（multicellular tumor spheroid MTS）的细胞毒性T淋巴细胞减少细胞因子的分泌。而对多细胞肿瘤球体的乳酸产生进行预处理则可以预防这个作用。

多细胞肿瘤球体是在体外应用组织培养方法 ,使肿瘤细胞以多细胞集聚体的形式生长 ,形成具有三维结构的细胞团。其在形态上类似肿瘤小结节,并且具有活体肿瘤组织的许多特点 ,如细胞紧密排列 ,延续性低氧细胞群及细胞异质性等。这些特征是其他体外培养所不具有的。ＭＴＳ在组织结构、生长动力学、对辐射、药物反应和宿主免疫反应等方面与实体瘤性质极为相似,故被称为肿瘤的体外模型。

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激活的细胞毒性T淋巴细胞利用糖酵解产能，并且依赖于把乳酸高效地排除细胞外，因为乳酸在细胞体内的积累会干扰它们的代谢。而把乳酸转运出细胞的单羧酸转运蛋白(MCT-1) 依赖于细胞内和细胞外的浓度梯度，当细胞外液的乳酸水平很高，浓度梯度降低或消失，乳酸从细胞内到细胞外的转运受阻，会导致细胞毒性T淋巴细胞（CTLs）的功能受损。研究人员得出结论，肿瘤环境的高乳酸浓度导致乳酸不能从细胞毒性T淋巴细胞排出，干扰了细胞的代谢和功能。这些发现提示，针对这个代谢路径是提高肿瘤免疫原性（从而被免疫细胞识别和杀灭）的一种很有希望的策略。

很多基础医学科学和医学相关的研究已经清楚表明，癌症绝不是绝症，既然癌症形成的原因和癌症的缺氧酸性本质已经明，彻底解读这个和其他实验的发现，就能悟出清晰的抗癌攻略。

　

参考文献

Inhibitory effect of tumor cell-derived lactic acid on human T cells

. - PubMed - NCBI  https://www.ncbi.nlm.nih.gov/pubmed/17255361
Department of Hematology and Oncology, University of Regensburg, Franz-Josef Strauss Allee 11, 93042 Regensburg, Germany.

A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid-free medium restored CTL function. CTLs infiltrating lactic acid-producing multicellular tumor spheroids showed a reduced cytokine production. Pretreatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells, thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity.