乳酸脱氢酶与肿瘤免疫代谢研究进展

doi:10.16689/j.cnki.cn11-9349/r.2020.04.004

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摘要不同免疫细胞亚群的代谢特征有所不同，抗肿瘤免疫细胞主要以有氧酵解和谷氨酰胺分解代谢提供代谢的物质与能量，而促进肿瘤发生和进展的抑制性免疫细胞亚群可利用肿瘤细胞代谢产物通过脂肪酸代谢等途径获取能量及中间产物。乳酸作为糖酵解途径的重要产物，直接或间接地影响肿瘤生物学行为，参与肿瘤免疫微环境调控。乳酸代谢的关键酶乳酸脱氢酶（LDH）常在肿瘤组织中高表达，是肿瘤微环境中连接各种免疫细胞代谢的关键酶之一，可激活某些信号传导途径和调控免疫应答参与肿瘤发生、发展。LDH水平升高主要由于肿瘤糖酵解活性增加和肿瘤缺氧坏死引起，其为免疫抑制性微环境的重要驱动者，LDH水平在一定程度上反映并可用于肿瘤糖酵解活性和免疫代谢状态的评估。本文对LDH与T淋巴细胞、巨噬细胞、树突状细胞等免疫细胞的代谢相关研究进行综述，旨在探究其在恶性肿瘤预后评估、抗肿瘤治疗尤其是免疫治疗疗效预测及监测中的可能应用。

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	周文丽
	缪明永

关键词 ：乳酸脱氢酶, 糖酵解, 肿瘤免疫代谢, 免疫治疗, 疗效预测

Abstract：The metabolic characteristics are different in different immune cell subsets. The immune cells in antitumor adaptive immunity mainly rely on aerobic glycolysis and glutamine catabolism to obtain energy and metabolites. Immunosuppressive cells in promoting cancer occurrence and progression can use the metabolites from cancer cells to get energy and intermediate products through fatty acid metabolism or other manners. As the critical product of glycolysis, lactic acid directly or indirectly affects the biological behavior of cancer and immunometabolism in tumor microenvironment. Lactate dehydrogenase （LDH） is a key enzyme connecting the metabolism of immune cells by lactic acid metabolism, generally with high expression in cancers, which regulates immune response and participates in carcinogenesis and development by activating some signal transduction pathway. It is identified as an important driver of immunosuppressive microenvironment. The increase of LDH level is mainly caused by the increase of glycolysis activity and hypoxia necrosis in cancer. To some extent, the levels of LDH can reflect and be used for the assessment of glycolysis activity and immune metabolism. However, the roles of LDH in immunometabolic regulation varies in different immune cells such as T lymphocytes, macrophages and dendritic cells. This paper reviews the researches on LDH and metabolism of these immune cells to explore the possible application in evaluating prognosis, predicting and monitoring efficacy of anti-tumor treatment, especially in cancer immunotherapy.

Key words： Lactate dehydrogenase Glycolysis Tumor immune metabolism Immunotherapy Efficacy prediction

基金资助:国家自然科学基金项目（81672888）

通讯作者: 缪明永，电子邮箱：miaomy@163.com

引用本文:

周文丽，缪明永. 乳酸脱氢酶与肿瘤免疫代谢研究进展[J]. 肿瘤代谢与营养电子杂志, 2020, 7(4): 396-401.
Zhou Wenli, Miao Mingyong. Research progress on lactatedehydrogenase and immunometabolism in cancer. Electron J Metab Nutr Cancer, 2020, 7(4): 396-401.

1.HANAHAN D, WEINBERG R A. Hallmarks of cancer: the next generation［J］. Cell, 2011, 144(5):646-674.
2.LIBERTI M V, LOCASALE J W. The warburg effect: how does it benefit cancer cells［J］? Trends Biochem Sci, 2016, 41(3):211-218.
3.FONDY T P, KAPLAN N O. Structural and functional properties of the H and M subunits of lactic dehydrogenases［J］. Ann N Y Acad Sci, 1965, 119(3):888-904.
4.MARKERT C L, SHAKLEE J B, WHITT G S. Evolution of a gene. Multiple genes for LDH isozymes provide a model of the evolution of gene structure, function and regulation［J］. Science, 1975, 189(4197):102-114.
5.KOUKOURAKIS M I, GIATROMANOLAKI A, SIVRIDIS E, et al. Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy［J］. Clin Cancer Res, 2011, 17(14):4892-4900.
6.JIA Z, ZHANG J, WANG Z, et al. An explorative analysis of the prognostic value of lactate dehydrogenase for survival and the chemotherapeutic response in patients with advanced triple-negative breast cancer［J］. Oncotarget, 2018, 9(12):10714-10722.
7.LIU X, MENG Q H, YE Y, et al. Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer［J］. Carcinogenesis, 2015, 36(2):243-248.
8.URBAN′SK A K, ORZECHOWSKI A. Unappreciated role of LDHA and LDHB to control apoptosis and autophagy in tumor cells［J］. Int J Mol Sci, 2019, 20(9):2085.
9.KOUKOURAKIS M I, GIATROMANOLAKI A, PANTELIADOU M, et al. Lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy［J］. Br J Cancer, 2014, 110(9):2217-2223.
10.LIU J, CHEN G, LIU Z, et al. Aberrant FGFR tyrosine kinase signaling enhances the warburg effect by reprogramming LDH isoform expression and activity in prostate cancer［J］. Cancer Res, 2018, 78(16):4459.
11.MCCLELAND M L, ADLER A S, SHANG Y, et al. An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer［J］. Cancer Res, 2012, 72(22):5812.
12.CUI J, QUAN M, JIANG W, et al. Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype［J］. Med Oncol, 2015, 32(5):143.
13.KURPIN′SK A A, SURAJ J, BONAR E, et al. Proteomic characterization of early lung response to breast cancer metastasis in mice［J］. Exp Mol Pathol, 2019, 107:129-140.
14.KIM J W, GAO P, LIU Y C, et al. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1［J］. Mol Cell Biol, 2007, 27(21):7381-7393.
15.CUI X G, HAN Z T, HE S H, et al. HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells［J］. Oncotarget, 2017, 8(15):24840-24852.
16.ZHAO Y H, ZHOU M, LIU H, et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth［J］. Oncogene, 2009, 28(42):3689-3701.
17.KIM H S, LEE H E, YANG H K, et al. High lactate dehydrogenase 5 expression correlates with high tumoral and stromal vascular endothelial growth factor expression in gastric cancer［J］. Pathobiology, 2014, 81(2):78-85.
18.KOUKOURAKIS M I, GIATROMANOLAKI A, SIVRIDIS E, et al. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the tumour angiogenesis research group［J］. J Clin Oncol, 2006, 24(26):4301-4308.
19.SCARTOZZI M, GIAMPIERI R, MACCARONI E, et al. Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients［J］. Br J Cancer, 2012, 106(5):799-804.
20.BUCK M D, SOWELL R T, KAECH S M, et al. Metabolic instruction of immunity［J］. Cell, 2017, 169(4):570-586.
21.THORSSON V, GIBBS D L, BROWN S D, et al. The immune landscape of cancer［J］. Immunity, 2018, 48(4):812-830.e814.
22.PEARCE E L, PEARCE E J. Metabolic pathways in immune cell activation and quiescence［J］. Immunity, 2013, 38(4):633-643.
23.DOMBLIDES C, LARTIGUE L, FAUSTIN B. Metabolic stress in the immune function of T cells, macrophages and dendritic cells［J］. Cells, 2018, 7(7):68.
24.BUCK M D, OSULLIVAN D, PEARCE E L. T cell metabolism drives immunity［J］. J Exp Med, 2015, 212(9):1345-1360.
25.CHANG C H, CURTIS J D, MAGGI LB, J R, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis［J］. Cell, 2013, 153(6):1239-1251.
26.HU Z, QU G, YU X, et al. Acylglycerol kinase maintains metabolic state and immune responses of CD8+ T cells［J］. Cell Metab, 2019, 30(2):290-302.e295.
27.GEIGER R, RIECKMANN J C, WOLF T, et al. L-Arginine modulates T cell metabolism and enhances survival and Anti-tumor activity［J］. Cell, 2016, 167(3):829-842.e813.
28.SHIME H, YABU M, AKAZAWA T, et al. Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway［J］. J Immunol, 2008, 180(11):7175-7183.
29.BRAND A, SINGER K, KOEHL G E, et al. LDHA-Associated lactic acid production blunts tumor immunosurveillance by T and NK cells［J］. Cell Metab, 2016, 24(5):657-671.
30.OHUE Y, NISHIKAWA H. Regulatory T (Treg) cells in cancer: can treg cells be a new therapeutic target［J］? Cancer Sci, 2019, 110(7):2080-2089.
31.KIM J H, KIM B S, LEE S K. Regulatory T cells in tumor microenvironment and approach for anticancer immunotherapy［J］. Immune Netw, 2020, 20(1)：e4.
32.SHANG B, LIU Y, JIANG S J, et al. Prognostic value of tumor-infiltrating FoxP3+regulatory T cells in cancers: a systematic review and meta-analysis［J］. Sci Rep, 2015, 5:15179-15179.
33.ANGELIN A, GIL-DE-GóMEZ L, DAHIYA S, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments［J］. Cell Metab, 2017, 25(6):1282-1293.e1287.
34.CHANMEE T, ONTONG P, KONNO K, et al. Tumor-associated macrophages as major players in the tumor microenvironment［J］. Cancers (Basel), 2014, 6(3):1670-1690.
35.HUGHES R, QIAN B Z, ROWAN C, et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy［J］. Cancer Res, 2015, 75(17):3479-3491.
36.COLEGIO O R, CHU N Q, SZABO A L, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid［J］. Nature, 2014, 513(7519):559-563.
37.ZHANG D, TANG Z, HUANG H, et al. Metabolic regulation of gene expression by histone lactylation［J］. Nature, 2019, 574(7779):575-580.
38.MARTíN P, DEL HOYO G M N, ANJURE F, et al. Concept of lymphoid versus myeloid dendritic cell lineages revisited: both CD8alpha(-) and CD8alpha(+) dendritic cells are generated from CD4(low) lymphoid-committed precursors［J］. Blood, 2000, 96(7):2511-2519.
39.PATENTE T A, PINHO M P, OLIVEIRA A A, et al. Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy［J］. Front Immunol, 2019, 9:3176.
40.KELLY B, ONEILL L A J. Metabolic reprogramming in macrophages and dendritic cells in innate immunity［J］. Cell Res, 2015, 25(7):771-784.
41.RYAN D G, ONEILL L A J. Krebs cycle rewired for macrophage and dendritic cell effector functions［J］. FEBS Lett, 2017, 591(19):2992-3006.
42.THWE P M, PELGROM L R, COOPER R, et al. Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming required for dendritic cell immune responses［J］. Cell Metab, 2017, 26(3):558-567.e555.
43.WCULEK S K, KHOUILI S C, PRIEGO E, et al. Metabolic control of dendritic cell functions: digesting information［J］. Front Immunol, 2019, 10:775.
44.GUAK H, AL HABYAN S, MA E H, et al. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration［J］. Nat Commun, 2018, 9(1):2463.
45.MALINARICH F, DUAN K, HAMID R A, et al. High mitochondrial respiration and glycolytic capacity represent a metabolic phenotype of human tolerogenic dendritic cells［J］. J Immunol, 2015, 194(11):5174-5186.
46.KRAWCZYK C M, HOLOWKA T, SUN J, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation［J］. Blood, 2010, 115(23):4742-4749.
47.CARONNI N, SIMONCELLO F, STAFETTA F, et al. Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer［J］. Cancer Res, 2018, 78(7):1685.
48.LARKIN J, MINOR D, DANGELO S, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigators choice chemotherapy in checkMate 037: A randomized, controlled, open-label phase Ⅲ trial［J］. J Clin Oncol, 2018, 36(4):383-390.
49.BRAHMER J, RECKAMP K L, BAAS P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer［J］. N Engl J Med, 2015, 373(2):123-135.
50.HODI F S, CHIARION-SILENI V, GONZALEZ R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial［J］. Lancet Oncol, 2018, 19(11):1480-1492.
51.OYA Y, YOSHIDA T, KURODA H, et al. Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer［J］. Oncotarget, 2017, 8(61):103117-103128.
52.JOSEPH R W, ELASSAISS-SCHAAP J, KEFFORD R, et al. Baseline tumor size is an independent prognostic factor for overall survival in patients with melanoma treated with pembrolizumab［J］. Clin Cancer Res, 2018, 24(20):4960.
53.AGARWALA S S, KEILHOLZ U, GILLES E, et al. LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951)［J］. Eur J Cancer, 2009, 45(10):1807-1814.