葛威祥, 严时佳, 万国辉. 乳酸在肿瘤微环境中的免疫调节作用J. 药学学报, 2022, 57(9): 2570-2579. DOI: 10.16438/j.0513-4870.2022-0519
引用本文: 葛威祥, 严时佳, 万国辉. 乳酸在肿瘤微环境中的免疫调节作用J. 药学学报, 2022, 57(9): 2570-2579. DOI: 10.16438/j.0513-4870.2022-0519
GE Wei-xiang, YAN Shi-jia, WAN Guo-hui. The immunomodulatory effect of lactic acid within the tumor microenvironmentJ. Acta Pharmaceutica Sinica, 2022, 57(9): 2570-2579. DOI: 10.16438/j.0513-4870.2022-0519
Citation: GE Wei-xiang, YAN Shi-jia, WAN Guo-hui. The immunomodulatory effect of lactic acid within the tumor microenvironmentJ. Acta Pharmaceutica Sinica, 2022, 57(9): 2570-2579. DOI: 10.16438/j.0513-4870.2022-0519

乳酸在肿瘤微环境中的免疫调节作用

The immunomodulatory effect of lactic acid within the tumor microenvironment

  • 摘要: 在氧气充足时, 肿瘤细胞会增加葡萄糖的摄取并将大量丙酮转化为乳酸。这种有氧糖酵解现象被称为Warburg效应(Warburg effect)。而产物乳酸作为癌细胞改造微环境的重要工具, 促进肿瘤侵袭与转移, 并通过诱导和招募免疫抑制相关细胞和分子, 有利于肿瘤发生发展。乳酸通过单羧酸转运蛋白从癌细胞流出并防止胞内酸化, 可抑制T淋巴细胞和NK (natural killer) 细胞的细胞毒活性, 并促进树突细胞(dendritic cells, DCs) 向分泌白介素10的耐受性DCs分化。此外, 通过组蛋白赖氨酸残基的乳酸化修饰, 乳酸可促进巨噬细胞向M2样表型极化, 从而抑制肿瘤微环境内的免疫反应。本综述从乳酸代谢过程、乳酸对免疫细胞的影响等方面系统地阐释了乳酸作为免疫抑制分子的作用。此外, 揭示了组蛋白乳酸化修饰在乳酸调节细胞代谢和功能中发挥的重要作用, 并探索了靶向乳酸代谢过程中的潜在靶点用于癌症治疗的可能性, 最终提出通过抑制糖酵解途径和乳酸生成与转运的相关蛋白的肿瘤免疫联合治疗策略。

     

    Abstract: Tumor cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate even under the circumstance of abundant oxygen. This phenomenon of aerobic glycolysis is known as the Warburg effect. Lactic acid, as an important tool for tumor cells to modify the tumor microenvironment, promotes the process of tumor invasion and metastasis, and contributes to tumor development by inducing and recruiting immunosuppression-related cells and molecules. Lactic acid could efflux out of the cancer cells via the monocarboxylate transporters to prevent intracellular acidification. Lactate can inhibit the cytolytic activity of T cells and natural killer (NK) cells, promoting the differentiation of tolerogenic interleukin 10 (IL-10)-producing dendritic cells. Moreover, the lactate-derived lactylation of histone lysine residues can promote macrophage polarization toward the M2-like phenotype, suppressing the immune response within the tumor microenvironment. In this review, we discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion from the aspects of lactic acid metabolism and its effect on immune cells. And we explore the possibility of targeting potential targets in lactate metabolism for tumor treatment. At last, we proposed a tumor immunotherapy strategy by inhibiting the pathway of aerobic glycolysis and proteins associated with the production and transport of lactic acid.

     

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