氨基酸代谢重编程对肝细胞癌免疫微环境的影响

刘晓丽; 谭钦文; 徐健; 陈焕灵; 余洁; 卢露; 戴明侃; 黄晶晶; 黄鸿娜; 毛德文

doi:10.12449/JCH241226

氨基酸代谢重编程对肝细胞癌免疫微环境的影响

DOI: 10.12449/JCH241226

刘晓丽¹,
谭钦文¹,
徐健¹,
陈焕灵¹,
余洁¹,
卢露¹,
戴明侃¹,
黄晶晶^2a, , ,,
黄鸿娜^2b,
毛德文^2c

1.
广西中医药大学研究生院，南宁 530200
2a.
广西中医药大学第一附属医院脾胃肝病科，南宁 530023
2b.
广西中医药大学第一附属医院中内教研室，南宁 530023
2c.
广西中医药大学第一附属医院肝病科，南宁 530023

基金项目:

国家自然科学基金 (82460957);

广西自然科学基金 (2024GXNSFDA010005);

广西自然科学基金 (2022GXNSFAA035460);

广西自然科学基金 (2022GXNSFBA035485);

广西中医药大学引进博士科研启动基金项目 (2022BS026);

广西研究生教育创新计划 (YCSW2023395)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：黄晶晶负责对研究思路的设计；余洁、卢露、戴明侃负责查阅相关文献；陈焕灵、徐健、谭钦文负责资料归纳与分析；刘晓丽负责绘图及撰写论文；毛德文、黄鸿娜负责指导修改论文及最后定稿。

详细信息

通信作者:
黄晶晶， 55869563@qq.com （ORCID： 0000-0002-4936-0838）

计量
- 文章访问数: 79
- HTML全文浏览量: 38
- PDF下载量: 10
- 被引次数: 0
出版历程
- 收稿日期: 2024-04-13
- 录用日期: 2024-07-04
- 出版日期: 2024-12-25

Effect of amino acid metabolic reprogramming on immune microenvironment of hepatocellular carcinoma

1.
Graduate School of Guangxi University of Chinese Medicine，Nanning 530200，China
2a.
Department of Spleen，Stomach and Hepatology，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China
2b.
Department of Traditional Chinese Internal Medicine，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China
2c.
Department of Hepatology，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China

Research funding:

National Natural Science Foundation of China (82460957);

Guangxi Natural Science Foundation (2024GXNSFDA010005);

Guangxi Natural Science Foundation (2022GXNSFAA035460);

Guangxi Natural Science Foundation (2022GXNSFBA035485);

Project of Introducing Doctoral Scientific Research Start-up Fund of Guangxi University of Traditional Chinese Medicine (2022BS026);

Guangxi Postgraduate Education Innovation Programme (YCSW2023395)

More Information

Corresponding author: HUANG Jingjing， 55869563@qq.com （ORCID： 0000-0002-4936-0838）

摘要

摘要: 肿瘤免疫微环境是由肿瘤免疫细胞及其分泌的细胞因子构成的肿瘤局部外环境，对肿瘤的发生和发展具有一定调控作用。在肝细胞癌的治疗中，氨基酸代谢及其对增殖细胞代谢的重编程日益受到关注，显示出在调控肿瘤免疫微环境中的潜力。尽管氨基酸代谢重编程被视为治疗肿瘤的新途径，但其在调控肝细胞癌中肿瘤免疫的具体机制尚未明确。本文深入探讨了氨基酸代谢在肝细胞癌肿瘤免疫微环境中的作用机制及其临床应用前景，旨在为肝癌的免疫治疗研究提供新的思路。
- 癌，肝细胞 /
- 肿瘤微环境 /
- 氨基酸类 /
- 代谢 /
- 免疫调节
Abstract: Tumor immune microenvironment is a local external tumor environment composed of tumor immune cells and the cytokines secreted by these cells， and it plays a regulatory role in the development and progression of tumors. In the treatment of hepatocellular carcinoma， amino acid metabolism and its reprogramming of proliferating cell metabolism have attracted more and more attention， showing potential in regulating the tumor immune microenvironment. Although amino acid metabolic reprogramming is regarded as a novel approach for tumor therapy， its specific mechanism remains unclear in the regulation of tumor immunity in hepatocellular carcinoma. This article discusses the mechanism of action of amino acid metabolism in the tumor immune microenvironment of hepatocellular carcinoma and its application prospect in clinical practice， in order to provide new ideas for immunotherapy for liver cancer.
- Carcinoma， Hepatocellular /
- Tumor Microenvironment /
- Amino Acids /
- Metabolism /
- Immunomodulation

HTML全文

图 1 氨基酸代谢重编程对HCC免疫微环境的影响

注： Cys，半胱氨酸；GLUD，谷氨酸脱氢酶；α-KG，α-酮戊二酸；BCAA，支链氨基酸；LAT，L型氨基酸转运蛋白；BCKA，支链氨基酸酮酸；Arg，精氨酸；PI3K，磷脂酰肌醇三激酶；MAT2A，Met腺苷转移酶Ⅱα；SAHH，S-腺苷同型半胱氨酸水解酶；SAM，S-腺苷甲硫氨酸；STAT5，信号传导及转录激活蛋白5。

Figure 1. Effects of reprogramming amino acid metabolism on the immune microenvironment in hepatocellular carcinoma

下载: 全尺寸图片幻灯片

参考文献(43)

[1]	ZHENG YL, LI L, JIA YX, et al. LINC01554-mediated glucose metabolism reprogramming suppresses tumorigenicity in hepatocellular carcinoma via downregulating PKM2 expression and inhibiting Akt/mTOR signaling pathway[J]. Theranostics, 2019, 9( 3): 796- 810. DOI: 10.7150/thno.28992.
[2]	RUMGAY H, ARNOLD M, FERLAY J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040[J]. J Hepatol, 2022, 77( 6): 1598- 1606. DOI: 10.1016/j.jhep.2022.08.021.
[3]	Department of Medical Emergency, National Health Commission of the People’s Republic of China. Healthy China action-implementation plan of cancer prevention action(2023-2030)[J]. China Cancer, 2023, 32( 12): 887- 890. DOI: 10.11735/j.issn.1004-0242.2023.12.A001. 中华人民共和国国家卫生健康委员会医疗应急司. 健康中国行动——癌症防治行动实施方案(2023—2030年)[J]. 中国肿瘤, 2023, 32( 12): 887- 890. DOI: 10.11735/j.issn.1004-0242.2023.12.A001.
[4]	NONG SQ, HAN XY, XIANG Y, et al. Metabolic reprogramming in cancer: Mechanisms and therapeutics[J]. MedComm(2020), 2023, 4( 2): e218. DOI: 10.1002/mco2.218.
[5]	FOGLIA B, BELTRÀ M, SUTTI S, et al. Metabolic reprogramming of HCC: A new microenvironment for immune responses[J]. Int J Mol Sci, 2023, 24( 8): 7463. DOI: 10.3390/ijms24087463.
[6]	PAGET S. The distribution of secondary growths in cancer of the breast. 1889[J]. Cancer Metastasis Rev, 1989, 8( 2): 98- 101.
[7]	ZHANG Q, LOU Y, BAI XL, et al. Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression[J]. World J Gastroenterol, 2018, 24( 31): 3500- 3512. DOI: 10.3748/wjg.v24.i31.3500.
[8]	KOTSARI M, DIMOPOULOU V, KOSKINAS J, et al. Immune system and hepatocellular carcinoma(HCC): New insights into HCC progression[J]. Int J Mol Sci, 2023, 24( 14): 11471. DOI: 10.3390/ijms241411471.
[9]	PAULUSMA CC, LAMERS WH, BROER S, et al. Amino acid metabolism, transport and signalling in the liver revisited[J]. Biochem Pharmacol, 2022, 201: 115074. DOI: 10.1016/j.bcp.2022.115074.
[10]	ZHENG Y, YAO YR, GE TX, et al. Amino acid metabolism reprogramming: Shedding new light on T cell anti-tumor immunity[J]. J Exp Clin Cancer Res, 2023, 42( 1): 291. DOI: 10.1186/s13046-023-02845-4.
[11]	ZHANG XH, ZHANG SY, LI L. Amino acid metabolic reprogramming in tumorigenesis and development[J]. Chin J Biochem Mol Biol, 2023, 39( 2): 174- 188. DOI: 10.13865/j.cnki.cjbmb.2022.06.1105. 张仙宏, 张思雨, 李乐. 氨基酸代谢重编程在肿瘤发生发展中的作用[J]. 中国生物化学与分子生物学报, 2023, 39( 2): 174- 188. DOI: 10.13865/j.cnki.cjbmb.2022.06.1105.
[12]	YANG F, HILAKIVI-CLARKE L, SHAHA A, et al. Metabolic reprogramming and its clinical implication for liver cancer[J]. Hepatology, 2023, 78( 5): 1602- 1624. DOI: 10.1097/HEP.0000000000000005.
[13]	WANG YY, BAI CS, RUAN YX, et al. Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia[J]. Nat Commun, 2019, 10( 1): 201. DOI: 10.1038/s41467-018-08033-9.
[14]	JIN HJ, WANG SY, ZAAL EA, et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer[J]. eLife, 2020, 9: e56749. DOI: 10.7554/eLife.56749.
[15]	LIN J, RAO DN, ZHANG M, et al. Metabolic reprogramming in the tumor microenvironment of liver cancer[J]. J Hematol Oncol, 2024, 17( 1): 6. DOI: 10.1186/s13045-024-01527-8.
[16]	TIAN LY, SMIT DJ, JÜCKER M. The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism[J]. Int J Mol Sci, 2023, 24( 3): 2652. DOI: 10.3390/ijms24032652.
[17]	MERLIN J, IVANOV S, DUMONT A, et al. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation[J]. Nat Metab, 2021, 3( 10): 1313- 1326. DOI: 10.1038/s42255-021-00471-y.
[18]	MA GF, ZHANG ZL, LI P, et al. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment[J]. Cell Commun Signal, 2022, 20( 1): 114. DOI: 10.1186/s12964-022-00909-0.
[19]	YE YY, YU BD, WANG H, et al. Glutamine metabolic reprogramming in hepatocellular carcinoma[J]. Front Mol Biosci, 2023, 10: 1242059. DOI: 10.3389/fmolb.2023.1242059.
[20]	PENG H, WANG YF, LUO WB. Multifaceted role of branched-chain amino acid metabolism in cancer[J]. Oncogene, 2020, 39( 44): 6747- 6756. DOI: 10.1038/s41388-020-01480-z.
[21]	BONVINI A, ROGERO MM, COQUEIRO AY, et al. Effects of different branched-chain amino acids supplementation protocols on the inflammatory response of LPS-stimulated RAW 264.7 macrophages[J]. Amino Acids, 2021, 53( 4): 597- 607. DOI: 10.1007/s00726-021-02940-w.
[22]	LING ZN, JIANG YF, RU JN, et al. Amino acid metabolism in health and disease[J]. Signal Transduct Target Ther, 2023, 8( 1): 345. DOI: 10.1038/s41392-023-01569-3.
[23]	HU GY, CUI Z, CHEN XY, et al. Suppressing mesenchymal stromal cell ferroptosis via targeting a metabolism-epigenetics axis corrects their poor retention and insufficient healing benefits in the injured liver milieu[J]. Adv Sci(Weinh), 2023, 10( 13): e2206439. DOI: 10.1002/advs.202206439.
[24]	MOSSMANN D, MÜLLER C, PARK S, et al. Arginine reprograms metabolism in liver cancer via RBM39[J]. Cell, 2023, 186( 23): 5068- 5083. DOI: 10.1016/j.cell.2023.09.011.
[25]	LÍNDEZ AA MI, REITH W. Arginine-dependent immune responses[J]. Cell Mol Life Sci, 2021, 78( 13): 5303- 5324. DOI: 10.1007/s00018-021-03828-4.
[26]	SICA A, PORTA C, MORLACCHI S, et al. Origin and functions of tumor-associated myeloid cells(TAMCs)[J]. Cancer Microenviron, 2012, 5( 2): 133- 149. DOI: 10.1007/s12307-011-0091-6.
[27]	YANG LM, CHU ZL, LIU M, et al. Amino acid metabolism in immune cells: Essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy[J]. J Hematol Oncol, 2023, 16( 1): 59. DOI: 10.1186/s13045-023-01453-1.
[28]	MISSIAEN R, ANDERSON NM, KIM LC, et al. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment[J]. Cell Metab, 2022, 34( 8): 1151- 1167. DOI: 10.1016/j.cmet.2022.06.010.
[29]	TRÉZÉGUET V, FATROUNI H, MERCHED AJ. Immuno-metabolic modulation of liver oncogenesis by the tryptophan metabolism[J]. Cells, 2021, 10( 12): 3469. DOI: 10.3390/cells10123469.
[30]	SOLVAY M, HOLFELDER P, KLAESSENS S, et al. Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes[J]. J Immunother Cancer, 2023, 11( 6): e006728. DOI: 10.1136/jitc-2023-006728.
[31]	CAMPESATO LF, BUDHU S, TCHAICHA J, et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine[J]. Nat Commun, 2020, 11( 1): 4011. DOI: 10.1038/s41467-020-17750-z.
[32]	DEY S, MONDAL A, DUHADAWAY JB, et al. IDO1 signaling through GCN2 in a subpopulation of gr-1⁺ cells shifts the IFNγ/IL6 balance to promote neovascularization[J]. Cancer Immunol Res, 2021, 9( 5): 514- 528. DOI: 10.1158/2326-6066.CIR-20-0226.
[33]	HEZAVEH K, SHINDE RS, KLÖTGEN A, et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity[J]. Immunity, 2022, 55( 2): 324- 340. DOI: 10.1016/j.immuni.2022.01.006.
[34]	GIRITHAR HN, STAATS PIRES A, AHN SB, et al. Involvement of the kynurenine pathway in breast cancer: Updates on clinical research and trials[J]. Br J Cancer, 2023, 129( 2): 185- 203. DOI: 10.1038/s41416-023-02245-7.
[35]	LONG G, WANG D, TANG JN, et al. Development of tryptophan metabolism patterns to predict prognosis and immunotherapeutic responses in hepatocellular carcinoma[J]. Aging(Albany NY), 2023, 15( 15): 7593- 7615. DOI: 10.18632/aging.204928.
[36]	PASCALE RM, PEITTA G, SIMILE MM, et al. Alterations of methionine metabolism as potential targets for the prevention and therapy of hepatocellular carcinoma[J]. Medicina(Kaunas), 2019, 55( 6): 296. DOI: 10.3390/medicina55060296.
[37]	ROY DG, CHEN J, MAMANE V, et al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming[J]. Cell Metab, 2020, 31( 2): 250- 266. DOI: 10.1016/j.cmet.2020.01.006.
[38]	HUNG MH, LEE JS, MA C, et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma[J]. Nat Commun, 2021, 12( 1): 1455. DOI: 10.1038/s41467-021-21804-1.
[39]	SINCLAIR LV, HOWDEN AJ, BRENES A, et al. Antigen receptor control of methionine metabolism in T cells[J]. eLife, 2019, 8: e44210. DOI: 10.7554/eLife.44210.
[40]	SAINI N, NAAZ A, METUR SP, et al. Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival[J]. Life Sci Alliance, 2022, 5( 12): e202201663. DOI: 10.26508/lsa.202201663.
[41]	LI JT, YANG H, LEI MZ, et al. Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA[J]. Signal Transduct Target Ther, 2022, 7( 1): 192. DOI: 10.1038/s41392-022-01017-8.
[42]	VOGEL A, MEYER T, SAPISOCHIN G, et al. Hepatocellular carcinoma[J]. Lancet, 2022, 400: 1345- 1362. DOI: 10.1016/S0140-6736(22)01200-4.
[43]	ENDICOTT M, JONES M, HULL J. Amino acid metabolism as a therapeutic target in cancer: A review[J]. Amino Acids, 2021, 53( 8): 1169- 1179. DOI: 10.1007/s00726-021-03052-1.