Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells
Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells
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DOI：
10.1007/s12195-020-00652-x
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发表时间：
2020-09-21
影响因子：
2.8
通讯作者：
Lewis, Jamal S.
中科院分区：
文献类型：
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作者：
Sangsuwan, Rapeepat;Thuamsang, Bhasirie;Lewis, Jamal S.
肿瘤分泌的乳酸不仅是一种副产物，而且是免疫细胞的一种活性调节剂。很少有研究旨在调查乳酸盐的真实作用，这通常与ph混淆。这样的知识差距需要解决。在此，我们研究了乳酸对树突状细胞（dc）和巨噬细胞（M phi s）的免疫调节作用。方法用50 mM乳酸钠（sLA）处理骨髓源性先天免疫细胞，37℃孵育2 d或5 d，对照组包括培养基、脂多糖（LPS）、MCT抑制剂（α -氰基-4-羟基肉桂酸和AR-C15585）。用特异性标记抗体和活力染料孵育细胞，流式细胞术分析免疫表型。使用limma- room对R进行差异表达分析，并使用Bejamini-Hochberg程序生成调整后的p值。结果乳酸暴露通过下调LPS刺激下CD80和MHCII的表达来减弱DC成熟。对于M phi s，乳酸暴露导致M2极化，M1标记物（CD38和iNOS）减少，CD163和Arg1表达增加。我们还发现单羧酸转运体（MCTs）在M phi s中介导乳酸效应的作用，MCT4抑制显著增强了乳酸M2极化，而MCT1/2阻断未能逆转乳酸的免疫抑制作用，这与基因表达结果相关，即乳酸增加了MCT4表达，但下调了MCT1/2的表达。结论本研究对代谢产物对肿瘤免疫的影响提供了有价值的见解，并将有助于确定新的代谢靶点，以增强癌症免疫治疗。
Introduction Lactate secreted by tumors is not just a byproduct, but rather an active modulator of immune cells. There are few studies aimed at investigating the true effect of lactate, which is normally confounded by pH. Such a knowledge gap needs to be addressed. Herein, we studied the immunomodulatory effects of lactate on dendritic cells (DCs) and macrophages (M phi s). Methods Bone marrow-derived innate immune cells were treated with 50 mM sodium lactate (sLA) and incubated for 2 days or 5 days at 37 degrees C. Controls included media, lipopolysaccharide (LPS), MCT inhibitors (alpha-cyano-4-hydroxycinnamic acid and AR-C15585). Flow cytometric analysis of immune phenotypes were performed by incubating cells with specific marker antibodies and viability dye. Differential expression analyses were conducted on R using limma-voom and adjusted p-values were generated using the Bejamini-Hochberg Procedure. Results Lactate exposure attenuated DC maturation through the downregulation of CD80 and MHCII expression under LPS stimulation. For M phi s, lactate exposure resulted in M2 polarization as evidenced by the reduction of M1 markers (CD38 and iNOS), and the increase in expression of CD163 and Arg1. We also revealed the role of monocarboxylate transporters (MCTs) in mediating lactate effect in M phi s. MCT4 inhibition significantly boosted lactate M2 polarization, while blocking of MCT1/2 failed to reverse the immunosuppressive effect of lactate, correlating with the result of gene expression that lactate increased MCT4 expression, but downregulated the expression of MCT1/2. Conclusions This research provides valuable insight on the influence of metabolic products on tumor immunity and will help to identify novel metabolic targets for augmenting cancer immunotherapies.