The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity-Immunometabolism-CSCIED科技核心评价数据库-手机版

The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity

The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity

ES评分 0 浏览量：704 下载量：0

DOI	10.1097/IN9.0000000000000014
刊名	Immunometabolism IJ
年，卷(期)	2023, 5(1)
作者	Wetzel, Tanner J.; Erfan, Sheila C.; Ananieva, Elitsa A.,
作者单位	[Wetzel, Tanner J.; Erfan, Sheila C.; Ananieva, Elitsa A.] Des Moines Univ, Dept Biochem & Nutr, 3200 Grand Ave, Des Moines, IA 50312 USA
摘要	Challenges regarding successful immunotherapy are associated with the heterogeneity of tumors and the complex interactions within the surrounding tumor microenvironment (TME), particularly those between immune and tumor cells. Of interest, T cells receive a myriad of environmental signals to elicit differentiation to effector subtypes, which is accompanied by metabolic reprogramming needed to satisfy the high energy and biosynthetic demands of their activated state. However, T cells are subjected to immunosuppressive signals and areas of oxygen and nutrient depletion in the TME, which causes T-cell exhaustion and helps tumor cells escape immune detection. The cytosolic and mitochondrial branched chain amino transferases, BCATc and BCATm, respectively, are responsible for the first step of the branched chain amino acid (BCAA) degradation, of which, metabolites are shunted into various metabolic processes. In recent years, BCAT isoenzymes have been investigated for their role in a variety of cancers found throughout the body; however, a gap of knowledge exists regarding the role BCAT isoenzymes play within immune cells of the TME. The aim of this review is to summarize recent findings about BCAAs and their catabolism at the BCAT step during T-cell metabolic reprogramming and to discuss the BCAT putative role in the anti-tumor immunity of T cells. Not only does this review acknowledges gaps pertaining to BCAA metabolism in the TME but it also identifies the practical application of BCAA metabolism in T cells in response to cancer and spotlights a potential target for pharmacological intervention.
Abstract	Challenges regarding successful immunotherapy are associated with the heterogeneity of tumors and the complex interactions within the surrounding tumor microenvironment (TME), particularly those between immune and tumor cells. Of interest, T cells receive a myriad of environmental signals to elicit differentiation to effector subtypes, which is accompanied by metabolic reprogramming needed to satisfy the high energy and biosynthetic demands of their activated state. However, T cells are subjected to immunosuppressive signals and areas of oxygen and nutrient depletion in the TME, which causes T-cell exhaustion and helps tumor cells escape immune detection. The cytosolic and mitochondrial branched chain amino transferases, BCATc and BCATm, respectively, are responsible for the first step of the branched chain amino acid (BCAA) degradation, of which, metabolites are shunted into various metabolic processes. In recent years, BCAT isoenzymes have been investigated for their role in a variety of cancers found throughout the body; however, a gap of knowledge exists regarding the role BCAT isoenzymes play within immune cells of the TME. The aim of this review is to summarize recent findings about BCAAs and their catabolism at the BCAT step during T-cell metabolic reprogramming and to discuss the BCAT putative role in the anti-tumor immunity of T cells. Not only does this review acknowledges gaps pertaining to BCAA metabolism in the TME but it also identifies the practical application of BCAA metabolism in T cells in response to cancer and spotlights a potential target for pharmacological intervention.
关键词	BCATc; BCATm; BCAA; leucine; immunotherapy; TME
KeyWord	BCATc; BCATm; BCAA; leucine; immunotherapy; TME
基金项目
页码	1-11

参考文献
相关文献

[1]. Dimberu PM, Leonhardt RM. Cancer immunotherapy takes a multi-faceted approach to kick the immune system into gear. Yale J Biol Med. 2011;84(4):371–80.

[2]. van der Woude LL, Gorris MAJ, Halilovic A, et al. Migrating into the tumor: a roadmap for T cells. Trends Cancer. 2017;3(11):797–808.

[3]. Rodgers TD, Barr PM. Pitfalls of combining novel agents in lymphoma. Curr Treat Options Oncol. 2018;19(7):35.

[4]. Grover NS, Savoldo B. Challenges of driving CD30-directed CAR-T cells to the clinic. BMC Cancer. 2019;19(1):203.

[5]. Onitilo AA, Wittig JA. Principles of immunotherapy in melanoma. Surg Clin North Am. 2020;100(1):161–73.

[6]. Vardhana S, Younes A. The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints. Haematologica. 2016;101(7):794–802.

[7]. Scharping NE, Delgoffe GM. Tumor microenvironment metabolism: a new checkpoint for anti-tumor immunity. Vaccines (Basel). 2016;4(4):46.

[8]. Lim AR, Rathmell WK, Rathmell JC. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife. 2020;9:e55185.

[9]. Arneth B. Tumor microenvironment. Medicina (Kaunas). 2019;56(1):15.

[10]. Castellano F, Correale J, Molinier-Frenkel V. Editorial. Immunosuppressive amino acid catabolizing enzymes in heallth and disease. Front Immunol. 2021;12:689864.

[11]. Lau AN, Heiden MGV. Metabolism in the tumor microenvironment. Ann Rev Cancer Biol. 2020;4(1):17–40.

[12]. Li GS, Huang HQ, Liang Y, et al. BCAT1: a risk factor in multiple cancers based on a pan-cancer analysis. Cancer Med. 2022;11(5):1396–412.

[13]. Dimitrov V, Barbier C, Ismailova A, et al. Vitamin D-regulated gene expression profiles: species-specificity and cell-specific effects on metabolism and immunity. Endocrinology. 2021;162(2):bqaa218.

[14]. Yi L, Fan X, Li J, et al. Enrichment of branched chain amino acid transaminase 1 correlates with multiple biological processes and contributes to poor survival of IDH1 wild-type gliomas. Aging (Albany NY). 2021;13(3):3645–60.

[15]. Peng H, Wang Y, Luo W. Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene. 2020;39(44):6747–56.

[16]. Mayers JR, Torrence ME, Danai LV, et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science. 2016;353(6304):1161–5.

[17]. Dey P, Baddour J, Muller F, et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature. 2017;542(7639):119–23.

[18]. Tönjes M, Barbus S, Park YJ, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med. 2013;19(7):901–8.

[19]. Shyer JA, Flavell RA, Bailis W. Metabolic signaling in T cells. Cell Res. 2020;30(8):649–59.

[20]. Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2020;20(1):55–70.

[21]. Mendoza A, Fang V, Chen C, et al. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature. 2017;546(7656):158–61.

[22]. Baixauli F, Acín-Pérez R, Villarroya-Beltrí C, et al. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab. 2015;22(3):485–98.

[23]. Tarasenko TN, Pacheco SE, Koenig MK, et al. Cytochrome c oxidase activity is a metabolic checkpoint that regulates cell fate decisions during T cell activation and differentiation. Cell Metab. 2017;25(6):1254–68.e1257.

[24]. Sabatini DM. Twenty-five years of mTOR: uncovering the link from nutrients to growth. Proc Natl Acad Sci USA. 2017;114(45):11818–25.

[25]. Yang K, Neale G, Green DR, et al. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol. 2011;12(9):888–97.

[26]. Pollizzi KN, Patel CH, Sun IH, et al. mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation. J Clin Invest. 2015;125(5):2090–108.

[27]. Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460(7251):108–12.

[28]. Pandit M, Timilshina M, Chang JH. LKB1-PTEN axis controls Th1 and Th17 cell differentiation via regulating mTORC1. J Mol Med (Berl). 2021;99(8):1139–50.

[29]. Shi H, Chapman NM, Wen J, et al. Amino acids license kinase mTORC1 activity and Treg cell function via small G proteins Rag and Rheb. Immunity. 2019;51(6):1012–27.e1017.

[30]. Ruterbusch M, Pruner KB, Shehata L, et al. In vivo CD4(+) T cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol. 2020;38:705–25.

[31]. van der Windt GJ, Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev. 2012;249(1):27–42.

[32]. Peng M, Yin N, Chhangawala S, et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science. 2016;354(6311):481–4.

[33]. Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186(6):3299–303.

[34]. Rashida Gnanaprakasam JN, Wu R, Wang R. Metabolic reprogramming in modulating T cell reactive oxygen species generation and antioxidant capacity. Front Immunol. 2018;9:1075.

[35]. Bhat P, Leggatt G, Waterhouse N, et al. Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. 2017;8(6):e2836.

[36]. Carr EL, Kelman A, Wu GS, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol. 2010;185(2):1037–44.

[37]. Sinclair LV, Rolf J, Emslie E, et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14(5):500–8.

[38]. Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832–44.

[39]. Park Y, Jin HS, Lopez J, et al. TSC1 regulates the balance between effector and regulatory T cells. J Clin Invest. 2013;123(12):5165–78.Google Scholar
[40]. Delgoffe GM, Pollizzi KN, Waickman AT, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295–303.

[41]. Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010;33(3):301–11.

[42]. Yang H, Yu Z, Chen X, et al. Structural insights into TSC complex assembly and GAP activity on Rheb. Nat Commun. 2021;12(1):339.

[43]. Pollizzi KN, Powell JD. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 2015;36(1):13–20.

[44]. Pompura SL, Wagner A, Kitz A, et al. Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis. J Clin Invest. 2021;131(2):e138519.

[45]. Buck MD, O’Sullivan D, Klein Geltink RI, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016;166(1):63–76.

[46]. Gerriets VA, Rathmell JC. Metabolic pathways in T cell fate and function. Trends Immunol. 2012;33(4):168–73.

[47]. Wei J, Long L, Yang K, et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol. 2016;17(3):277–85.

[48]. Ananieva EA, Powell JD, Hutson SM. Leucine metabolism in T cell activation: mTOR signaling and beyond. Adv Nutr. 2016;7(4): 798s–805S.

[49]. Saxton RA, Knockenhauer KE, Wolfson RL, et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2016;351(6268):53–8.

[50]. Chen J, Ou Y, Luo R, et al. SAR1B senses leucine levels to regulate mTORC1 signalling. Nature. 2021;596(7871):281–4.

[51]. Wang LX, Zhu XM, Yao YM. Sestrin2: Its potential role and regulatory mechanism in host immune response in diseases. Front Immunol. 2019;10:2797.

[52]. Sané AT, Seidman E, Peretti N, et al. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture. Arterioscler Thromb Vasc Biol. 2017;37(12):2243–51.

[53]. Zheng Y, Delgoffe GM, Meyer CF, et al. Anergic T cells are metabolically anergic. J Immunol. 2009;183(10):6095–101.

[54]. Ananieva EA, Patel CH, Drake CH, et al. Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J Biol Chem. 2014;289(27):18793–804.

[55]. Hidayat S, Yoshino K, Tokunaga C, et al. Inhibition of amino acid-mTOR signaling by a leucine derivative induces G1 arrest in Jurkat cells. Biochem Biophys Res Commun. 2003;301(2):417–23.

[56]. Fotiadis D, Kanai Y, Palacín M. The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med. 2013;34(2-3):139–58.

[57]. Ikeda K, Kinoshita M, Kayama H, et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep. 2017;21(7):1824–38.

[58]. Cobbold SP, Adams E, Farquhar CA, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA. 2009;106(29):12055–60.

[59]. Hayashi K, Jutabha P, Endou H, et al. LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells. J Immunol. 2013;191(8):4080–5.

[60]. Nicklin P, Bergman P, Zhang B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136(3):521–34.

[61]. Hutson SM, Fenstermacher D, Mahar C. Role of mitochondrial transamination in branched chain amino acid metabolism. J Biol Chem. 1988;263(8):3618–25.

[62]. Ichihara A, Koyama E. Transaminase of branched chain amino acids. I. Branched chain amino acids-alpha-ketoglutarate transaminase. J Biochem. 1966;59(2):160–9.

[63]. Ye Z, Wang S, Zhang C, et al. Coordinated modulation of energy metabolism and inflammation by branched-chain amino acids and fatty acids. Front Endocrinol (Lausanne). 2020;11:617.

[64]. Luu M, Visekruna A. Short-chain fatty acids: bacterial messengers modulating the immunometabolism of T cells. Eur J Immunol. 2019;49(6):842–8.

[65]. He A, Chen X, Tan M, et al. Acetyl-CoA derived from hepatic peroxisomal β-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation. Mol Cell. 2020;79(1):30–42.e34.

[66]. Son SM, Park SJ, Lee H, et al. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab. 2019;29(1):192–201.e197.

[67]. García-Espinosa MA, Wallin R, Hutson SM, et al. Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids. J Neurochem. 2007;100(6):1458–68.

[68]. Pearce EL, Poffenberger MC, Chang CH, et al. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342(6155):1242454.

[69]. Martin SB, Reiche WS, Fifelski NA, et al. Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling. Biochem J. 2020;477(9):1579–99.

[70]. Ananieva EA, Bostic JN, Torres AA, et al. Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma. Br J Cancer. 2018;119(8):1009–17.

[71]. Liu Y, Xu R, Gu H, et al. Metabolic reprogramming in macrophage responses. Biomark Res. 2021;9(1):1.

[72]. Papathanassiu AE, Ko JH, Imprialou M, et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat Commun. 2017;8:16040.

[73]. Ko JH, Olona A, Papathanassiu AE, et al. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages. J Cell Sci. 2020;133(22):jcs247957.

[74]. Graham C, Jozwik A, Pepper A, et al. Allogeneic CAR-T cells: more than ease of access? Cells. 2018;7(10):155.

[75]. Lyssiotis CA, Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 2017;27(11):863–75.

[76]. Ye Z, Yue L, Shi J, et al. Role of IDO and TDO in cancers and related diseases and the therapeutic implications. J Cancer. 2019;10(12):2771–82.

[77]. Salminen A. Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. J Mol Med (Berl). 2021;99(11):1553–69.

[78]. Oh MH, Sun IH, Zhao L, et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest. 2020;130(7):3865–84.

[79]. Reinfeld BI, Madden MZ, Wolf MM, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature. 2021;593(7858):282–8.

[80]. Leone RD, Zhao L, Englert JM, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019;366(6468):1013–21.

[81]. Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care. 2018;21(1):64–70.

[82]. Mo BY, Li GS, Huang SN, et al. The underlying molecular mechanism and identification of transcription factor markers for laryngeal squamous cell carcinoma. Bioengineered. 2021;12(1):208–24.

[83]. Eckerle S, Brune V, Döring C, et al. Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma. Leukemia. 2009;23(11):2129–38.

[84]. Crescenzo R, Abate F, Lasorsa E, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27(4):516–32.

[85]. Silva LS, Poschet G, Nonnenmacher Y, et al. Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype. EMBO Rep. 2017;18(12):2172–85.

[86]. Choi BD, Curry WT. IDH mutational status and the immune system in gliomas: a tale of two tumors? Transl Cancer Res. 2017;6(Suppl 7):S1253–6.

[87]. Yuan Q, Zuo FX, Cai HQ, et al. Identifying differential expression genes and prognostic signature based on subventricular zone involved glioblastoma. Front Genet. 2022;13:912227.

[88]. Guri Y, Nordmann TM, Roszik J. mTOR at the transmitting and receiving ends in tumor immunity. Front Immunol. 2018;9:578.

[89]. Monteiro AR, Hill R, Pilkington GJ, et al. The role of hypoxia in glioblastoma invasion. Cells. 2017;6(4):45.

[90]. Zhang B, Chen Y, Shi X, et al. Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma. Cell Mol Life Sci. 2021;78(1):195–206.

[91]. Zhang B, Chen Y, Bao L, et al. GPT2 is induced by hypoxia-inducible factor (HIF)-2 and promotes glioblastoma growth. Cells. 2022;11(16):2597.

[92]. Conway ME, Hull J, El Hindy M, et al. Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH-WT gliomas. Brain Pathol. 2016;26(6):789–91.

[93]. Li JT, Li KY, Su Y, et al. Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization. Natl Sci Rev. 2022;9(5):nwab212.

[94]. Michelucci A, Cordes T, Ghelfi J, et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci USA. 2013;110(19):7820–5.

[95]. Weiss JM, Davies LC, Karwan M, et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J Clin Invest. 2018;128(9):3794–805.

引用本文

Wetzel, Tanner J.; Erfan, Sheila C.; Ananieva, Elitsa A.. The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity [J]. Immunometabolism. 2023; 5; (1). 1 - 11.

文献评论

相关学者

相关机构