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Metabolic profiles of regulatory T cells in the tumour microenvironment

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Abstract

Metabolic reprogramming of cancer cells generates a tumour microenvironment (TME) characterised by nutrient restriction, hypoxia, acidity and oxidative stress. While these conditions are unfavourable for infiltrating effector T cells, accumulating evidence suggests that regulatory T cells (Tregs) continue to exert their immune-suppressive functions within the TME. The advantages of Tregs within the TME stem from their metabolic profile. Tregs rely on oxidative phosphorylation for their functions, which can be fuelled by a variety of substrates. Even though Tregs are an attractive target to augment anti-tumour immune responses, it remains a challenge to specifically target intra-tumoral Tregs. We provide a comprehensive review of distinct mechanistic links and pathways involved in regulation of Treg metabolism under the prevailing conditions within the tumour. We also describe how these Tregs differ from the ones in the periphery, and from conventional T cells in the tumour. Targeting pathways responsible for adaptation of Tregs in the tumour microenvironment improves anti-tumour immunity in preclinical models. This may provide alternative therapies aiming at reducing immune suppression in the tumour.

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Abbreviations

AHR:

Aryl hydrocarbon receptor

BCAA:

Branched-chain amino acids

ETC:

Electron transport chain

FAO:

Fatty acid oxidation

FAS:

Fatty acid synthesis

HIF:

Hypoxia-inducible factor

IDO:

Indoleamine 2, 3-dioxygenase

iTreg:

Induced Tregs

mTOR:

Mammalian target of rapamycin

nTregs:

Natural Tregs

OXPHOS:

Oxidative phosphorylation

RHOA:

Ras homolog family member A

ROS:

Reactive oxygen species

TCA:

Tri-carboxylic acid

Tconv:

Conventional T cells

TGF-β:

Transforming growth factor beta

TI-Tregs:

Tumour-infiltrating Tregs

TME:

Tumour microenvironment

Treg:

Regulatory T cells

WT:

Wild-type

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  2. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530. https://doi.org/10.1085/jgp.8.6.519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weinberg F, Hamanaka R, Wheaton WW et al (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107:8788–8793. https://doi.org/10.1073/pnas.1003428107

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yang LV (2017) Tumor microenvironment and metabolism. Int J Mol Sci 18:278

    Article  PubMed Central  Google Scholar 

  5. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634

    Article  CAS  PubMed  Google Scholar 

  6. Huber V, Camisaschi C, Berzi A et al (2017) Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol 43:74–89

    Article  CAS  PubMed  Google Scholar 

  7. Longo DL, Bartoli A, Consolino L et al (2016) In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging. Cancer Res 76:6463–6470. https://doi.org/10.1158/0008-5472.CAN-16-0825

    Article  CAS  PubMed  Google Scholar 

  8. Storz P (2005) Reactive oxygen species in tumor progression. Front Biosci 10:1881–1896

    Article  CAS  PubMed  Google Scholar 

  9. Yao CH, Wang R, Wang Y et al (2019) Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation. Elife. https://doi.org/10.7554/eLife.41351

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen Y, McMillan-Ward E, Kong J et al (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 15:171–182. https://doi.org/10.1038/sj.cdd.4402233

    Article  CAS  PubMed  Google Scholar 

  11. DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2:e1600200–e1600200. https://doi.org/10.1126/sciadv.1600200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lieu EL, Nguyen T, Rhyne S, Kim J (2020) Amino acids in cancer. Exp Mol Med 52:15–30. https://doi.org/10.1038/s12276-020-0375-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23(1):27–47. https://doi.org/10.1016/j.cmet.2015.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lacroix R, Rozeman EA, Kreutz M et al (2018) Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol Immunother 67:1331–1348. https://doi.org/10.1007/s00262-018-2195-z

    Article  CAS  PubMed  Google Scholar 

  15. Chang CH, Qiu J, O’Sullivan D et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241. https://doi.org/10.1016/j.cell.2015.08.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ho P-C, Bihuniak JD, Macintyre AN et al (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–1228. https://doi.org/10.1016/j.cell.2015.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lim AR, Rathmell WK, Rathmell JC (2020) The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife 9:e55185. https://doi.org/10.7554/eLife.55185

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bhattacharyya S, Saha J (2015) Tumour, oxidative stress and host T cell response: cementing the dominance. Scand J Immunol 82:477–488. https://doi.org/10.1111/sji.12350

    Article  CAS  PubMed  Google Scholar 

  19. Yuan X, Cheng G, Malek TR (2014) The importance of regulatory T-cell heterogeneity in maintaining self-tolerance. Immunol Rev 259:103–114. https://doi.org/10.1111/imr.12163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sakaguchi S, Ono M, Setoguchi R et al (2006) Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27

    Article  CAS  PubMed  Google Scholar 

  21. Vaeth M, Wang YH, Eckstein M et al (2019) Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels. Nat Commun 10:1–16. https://doi.org/10.1038/s41467-019-08959-8

    Article  CAS  Google Scholar 

  22. Andersson J, Tran DQ, Pesu M et al (2008) CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med 205:1975–1981. https://doi.org/10.1084/jem.20080308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Feuerer M, Hill JA, Mathis D, Benoist C (2009) Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 10:689–695. https://doi.org/10.1038/ni.1760

    Article  CAS  PubMed  Google Scholar 

  24. Zhou G, Levitsky HI (2007) Natural regulatory T cells and De novo-induced regulatory T Cells contribute independently to tumor-specific tolerance. J Immunol 178:2155–2162. https://doi.org/10.4049/jimmunol.178.4.2155

    Article  CAS  PubMed  Google Scholar 

  25. Waight JD, Takai S, Marelli B et al (2015) Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4 + regulatory T cells in tumors from mice and humans. J Immunol 194:878–882. https://doi.org/10.4049/jimmunol.1402725

    Article  CAS  PubMed  Google Scholar 

  26. Ahmadzadeh M, Pasetto A, Jia L et al (2019) Tumor-infiltrating human CD4(+) regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity. Sci Immunol. https://doi.org/10.1126/sciimmunol.aao4310

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zheng Y, Josefowicz S, Chaudhry A et al (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–812. https://doi.org/10.1038/nature08750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moo-Young TA, Larson JW, Belt BA et al (2009) Tumor-derived TGF-beta mediates conversion of CD4+Foxp3+ regulatory T cells in a murine model of pancreas cancer. J Immunother 32:12–21. https://doi.org/10.1097/CJI.0b013e318189f13c

    Article  CAS  PubMed  Google Scholar 

  29. Walker LSK, Sansom DM (2011) The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11:852–863

    Article  CAS  PubMed  Google Scholar 

  30. Schmidt A, Oberle N, Krammer PH (2012) Molecular mechanisms oftreg-mediatedt cell suppression. Front Immunol 3:51

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumar P, Bhattacharya P, Prabhakar BS (2018) A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 95:77–99. https://doi.org/10.1016/j.jaut.2018.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shang B, Liu Y, Jiang SJ, Liu Y (2015) Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Sci Rep. https://doi.org/10.1038/srep15179

    Article  PubMed  PubMed Central  Google Scholar 

  33. Rasku MA, Clem AL, Telang S et al (2008) Transient T cell depletion causes regression of melanoma metastases. J Transl Med. https://doi.org/10.1186/1479-5876-6-12

    Article  PubMed  PubMed Central  Google Scholar 

  34. Fisher SA, Aston WJ, Chee J et al (2017) Transient Treg depletion enhances therapeutic anti-cancer vaccination: immunity. Inflamm Dis 5:16–28. https://doi.org/10.1002/iid3.136

    Article  CAS  Google Scholar 

  35. Teng MWL, Ngiow SF, von Scheidt B et al (2010) Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth. Cancer Res 70:7800–7809. https://doi.org/10.1158/0008-5472.CAN-10-1681

    Article  CAS  PubMed  Google Scholar 

  36. Arce Vargas F, Furness AJS, Solomon I et al (2017) Fc-Optimized Anti-CD25 depletes tumor-infiltrating regulatory T Cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46:577–586. https://doi.org/10.1016/j.immuni.2017.03.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rech AJ, Mick R, Martin S et al (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 4:13462–13462. https://doi.org/10.1126/scitranslmed.3003330

    Article  CAS  Google Scholar 

  38. Jacobs JFM, Punt CJA, Lesterhuis WJ et al (2010) Dendritic cell vaccination in combination with Anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin Cancer Res 16:5067–5078. https://doi.org/10.1158/1078-0432.CCR-10-1757

    Article  CAS  PubMed  Google Scholar 

  39. Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–197. https://doi.org/10.1038/ni1428

    Article  CAS  PubMed  Google Scholar 

  40. Barbi J, Pardoll D, Pan F (2013) Metabolic control of the Treg/Th17 axis. Immunol Rev 252:52–77. https://doi.org/10.1111/imr.12029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gerriets VA, Kishton RJ, Nichols AG et al (2015) Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest 125:194–207. https://doi.org/10.1172/JCI76012

    Article  PubMed  Google Scholar 

  42. Gerriets VA, Kishton RJ, Johnson MO et al (2016) Foxp3 and toll-like receptor signaling balance T reg cell anabolic metabolism for suppression. Nat Immunol 17:1459–1466. https://doi.org/10.1038/ni.3577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Michalek RD, Gerriets VA, Jacobs SR et al (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4 + T cell subsets. J Immunol 186:3299–3303. https://doi.org/10.4049/jimmunol.1003613

    Article  CAS  PubMed  Google Scholar 

  44. Berod L, Friedrich C, Nandan A et al (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20:1327–1333. https://doi.org/10.1038/nm.3704

    Article  CAS  PubMed  Google Scholar 

  45. Almeida L, Lochner M, Berod L, Sparwasser T (2016) Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol 28:514–524

    Article  CAS  PubMed  Google Scholar 

  46. O’Neill LAJ, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16:553–565. https://doi.org/10.1038/nri.2016.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang A, Luan HH, Medzhitov R (2019) An evolutionary perspective on immunometabolism. Science 363(6423):eaar3932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Salmond RJ (2018) mTOR regulation of glycolytic metabolism in T cells. Front Cell Dev Biol 6:122

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kishore M, Cheung KCP, Fu H et al (2017) Regulatory T Cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47:875-889.e10. https://doi.org/10.1016/j.immuni.2017.10.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Weinberg SE, Singer BD, Steinert EM et al (2019) Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565:495–499. https://doi.org/10.1038/s41586-018-0846-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. He N, Fan W, Henriquez B et al (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci USA 114:12542–12547. https://doi.org/10.1073/pnas.1715363114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang K, Blanco DB, Neale G et al (2017) Homeostatic control of metabolic and functional fitness of T(reg) cells by LKB1 signalling. Nature 548:602–606. https://doi.org/10.1038/nature23665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Field CS, Baixauli F, Kyle RL et al (2020) Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab 31:422-437.e5. https://doi.org/10.1016/j.cmet.2019.11.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Angelin A, Gil-de-Gómez L, Dahiya S et al (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25:1282-1293.e7. https://doi.org/10.1016/j.cmet.2016.12.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang R, Dillon CP, Shi LZ et al (2011) The transcription factor myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882. https://doi.org/10.1016/j.immuni.2011.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Charbonnier L-M, Cui Y, Stephen-Victor E et al (2019) Functional reprogramming of regulatory T cells in the absence of Foxp3. Nat Immunol 20:1208–1219. https://doi.org/10.1038/s41590-019-0442-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kareva I (2019) Metabolism and gut microbiota in cancer immunoediting, CD8/Treg ratios, immune cell homeostasis, and cancer (immuno)therapy: concise review. Stem Cells 37:1273–1280. https://doi.org/10.1002/stem.3051

    Article  PubMed  Google Scholar 

  59. Pacella I, Procaccini C, Focaccetti C et al (2018) Fatty acid metabolism complements glycolysis in th selective regulatory t cell expansion during tumor growth. Proc Natl Acad Sci USA 115:E6546–E6555. https://doi.org/10.1073/pnas.1720113115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Miska J, Lee-Chang C, Rashidi A et al (2019) HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of Tregs in glioblastoma. Cell Rep 27:226–237. https://doi.org/10.1016/j.celrep.2019.03.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang H, Franco F, Tsui YC et al (2020) CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 21:298–308. https://doi.org/10.1038/s41590-019-0589-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kumagai S, Togashi Y, Sakai C et al (2020) An oncogenic alteration creates a microenvironment that promotes tumor progression by conferring a metabolic advantage to regulatory T cells. Immunity 53:187-203.e8. https://doi.org/10.1016/j.immuni.2020.06.016

    Article  CAS  PubMed  Google Scholar 

  63. Li L, Liu X, Sanders KL et al (2019) TLR8-mediated metabolic control of human Treg function: a mechanistic target for cancer immunotherapy. Cell Metab 29:103–123. https://doi.org/10.1016/j.cmet.2018.09.020

    Article  CAS  PubMed  Google Scholar 

  64. Klysz D, Tai X, Robert PA et al (2015) Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal. https://doi.org/10.1126/scisignal.aab2610

    Article  PubMed  Google Scholar 

  65. Cobbold SP, Adams E, Farquhar CA et al (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA 106:12055–12060. https://doi.org/10.1073/pnas.0903919106

    Article  PubMed  PubMed Central  Google Scholar 

  66. Metzler B, Gfeller P, Guinet E (2016) Restricting glutamine or glutamine-dependent purine and pyrimidine syntheses promotes human T cells with High FOXP3 expression and regulatory properties. J Immunol 196:3618–3630. https://doi.org/10.4049/jimmunol.1501756

    Article  CAS  PubMed  Google Scholar 

  67. Fallarino F, Volpi C, Fazio F et al (2010) Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat Med 16:897–902. https://doi.org/10.1038/nm.2183

    Article  CAS  PubMed  Google Scholar 

  68. Long Y, Tao H, Karachi A et al (2020) Dysregulation of glutamate transport enhances Treg function that promotes vegf blockade resistance in glioblastoma. Cancer Res 80:499–509. https://doi.org/10.1158/0008-5472.CAN-19-1577

    Article  CAS  PubMed  Google Scholar 

  69. Altman BJ, Stine ZE, Dang CV (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16:619–634. https://doi.org/10.1038/nrc.2016.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Timmerman LA, Holton T, Yuneva M et al (2013) Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24:450–465. https://doi.org/10.1016/j.ccr.2013.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Uyttenhove C, Pilotte L, Théate I et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274. https://doi.org/10.1038/nm934

    Article  CAS  PubMed  Google Scholar 

  72. Sharma MD, Hou D-Y, Liu Y et al (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113:6102–6111. https://doi.org/10.1182/blood-2008-12-195354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Baban B, Chandler PR, Sharma MD et al (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475–2483. https://doi.org/10.4049/jimmunol.0900986

    Article  CAS  PubMed  Google Scholar 

  74. Yan Y, Zhang G-X, Gran B et al (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185:5953–5961. https://doi.org/10.4049/jimmunol.1001628

    Article  CAS  PubMed  Google Scholar 

  75. Sharma MD, Baban B, Chandler P et al (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117:2570–2582. https://doi.org/10.1172/JCI31911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Opitz CA, Litzenburger UM, Sahm F et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203. https://doi.org/10.1038/nature10491

    Article  CAS  PubMed  Google Scholar 

  77. Mezrich JD, Fechner JH, Zhang X et al (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185:3190–3198. https://doi.org/10.4049/jimmunol.0903670

    Article  CAS  PubMed  Google Scholar 

  78. Campesato LF, Budhu S, Tchaicha J et al (2020) Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat Commun 11:4011. https://doi.org/10.1038/s41467-020-17750-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lowe MM, Boothby I, Clancy S et al (2019) Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. https://doi.org/10.1172/jci.insight.129756

    Article  PubMed  PubMed Central  Google Scholar 

  80. Ikeda K, Kinoshita M, Kayama H et al (2017) Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep 21:1824–1838. https://doi.org/10.1016/j.celrep.2017.10.082

    Article  CAS  PubMed  Google Scholar 

  81. Ananieva EA, Wilkinson AC (2018) Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care 21:64–70. https://doi.org/10.1097/MCO.0000000000000430

    Article  CAS  PubMed  Google Scholar 

  82. Sivanand S, Vander Heiden MG (2020) Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell 37:147–156. https://doi.org/10.1016/j.ccell.2019.12.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ren L, Yu Y, Wang L et al (2016) Hypoxia-induced CCL28 promotes recruitment of regulatory T cells and tumor growth in liver cancer. Oncotarget 7:75763–75773. https://doi.org/10.18632/oncotarget.12409

    Article  PubMed  PubMed Central  Google Scholar 

  84. Facciabene A, Peng X, Hagemann IS et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T reg cells. Nature 475:226–230. https://doi.org/10.1038/nature10169

    Article  CAS  PubMed  Google Scholar 

  85. Clambey ET, McNamee EN, Westrich JA et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA 109:E2784. https://doi.org/10.1073/pnas.1202366109

    Article  PubMed  PubMed Central  Google Scholar 

  86. Deng B, Zhu J-M, Wang Y et al (2013) Intratumor hypoxia promotes immune tolerance by inducing regulatory T cells via TGF-β1 in gastric cancer. PLoS ONE 8:e63777. https://doi.org/10.1371/journal.pone.0063777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ben-Shoshan J, Maysel-Auslender S, Mor A et al (2008) Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1α. Eur J Immunol 38:2412–2418. https://doi.org/10.1002/eji.200838318

    Article  CAS  PubMed  Google Scholar 

  88. Westendorf A, Skibbe K, Adamczyk A et al (2017) Hypoxia enhances immunosuppression by Inhibiting CD4+ Effector T cell function and promoting Treg activity. Cell Physiol Biochem 41:1271–1284. https://doi.org/10.1159/000464429

    Article  CAS  PubMed  Google Scholar 

  89. Papandreou I, Cairns RA, Fontana L et al (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197. https://doi.org/10.1016/j.cmet.2006.01.012

    Article  CAS  PubMed  Google Scholar 

  90. Fischer K, Hoffmann P, Voelkl S et al (2007) Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood 109:3812–3819. https://doi.org/10.1182/blood-2006-07-035972

    Article  CAS  PubMed  Google Scholar 

  91. Calcinotto A, Filipazzi P, Grioni M et al (2012) Modulation of microenvironment acidity reverses energy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 72:2746–2756. https://doi.org/10.1158/0008-5472.CAN-11-1272

    Article  PubMed  Google Scholar 

  92. Maj T, Wang W, Crespo J et al (2017) Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 18:1332–1341. https://doi.org/10.1038/ni.3868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mougiakakos D, Johansson CC, Jitschin R et al (2011) Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood 117:857–861. https://doi.org/10.1182/blood-2010-09-307041

    Article  CAS  PubMed  Google Scholar 

  94. Kurniawan H, Franchina DG, Guerra L et al (2020) Glutathione restricts serine metabolism to preserve regulatory T Cell function. Cell Metab 31:920-936.e7. https://doi.org/10.1016/j.cmet.2020.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lu SC (2009) Regulation of glutathione synthesis. Mol Aspects Med 30:42–59. https://doi.org/10.1016/j.mam.2008.05.005

    Article  CAS  PubMed  Google Scholar 

  96. Garg SK, Yan Z, Vitvitsky V, Banerjee R (2011) Differential dependence on cysteine from transsulfuration versus transport during T cell activation. Antioxid Redox Signal 15:39–47. https://doi.org/10.1089/ars.2010.3496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhu J, Berisa M, Schwörer S et al (2019) Transsulfuration activity can support cell growth upon extracellular cysteine limitation. Cell Metab 30:865-876.e5. https://doi.org/10.1016/j.cmet.2019.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cieslewicz M, Mahalingam D, Harb WA et al (2019) A phase I open label study evaluating VT1021 in patients with advanced solid tumors. J Clin Oncol 37:TPS3158. https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS3158

    Article  Google Scholar 

  99. Raud B, Roy DG, Divakaruni AS et al (2018) Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab 28:504-515.e7. https://doi.org/10.1016/j.cmet.2018.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. O’Connor RS, Guo L, Ghassemi S et al (2018) The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci Rep 8:6289. https://doi.org/10.1038/s41598-018-24676-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yao C-H, Liu G-Y, Wang R et al (2018) Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation. PLoS Biol 16:e2003782. https://doi.org/10.1371/journal.pbio.2003782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yu Y-R, Imrichova H, Wang H et al (2020) Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat Immunol. https://doi.org/10.1038/s41590-020-0793-3

    Article  PubMed  PubMed Central  Google Scholar 

  103. Scharping NE, Menk AV, Moreci RS et al (2016) The tumor microenvironment represses T Cell mitochondrial biogenesis to drive intratumoral T Cell metabolic insufficiency and dysfunction. Immunity 45:374–388. https://doi.org/10.1016/j.immuni.2016.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Fischer M, Bantug GR, Dimeloe S et al (2018) Early effector maturation of naïve human CD8(+) T cells requires mitochondrial biogenesis. Eur J Immunol 48:1632–1643. https://doi.org/10.1002/eji.201747443

    Article  CAS  PubMed  Google Scholar 

  105. Zappasodi R, Serganova I, Cohen I et al (2020) Abstract 3257: CTLA-4 blockade drives loss of regulatory T cell functional stability in glycolysis defective tumors. Cancer Res 80:3257–3257. https://doi.org/10.1158/1538-7445.AM2020-3257

    Article  Google Scholar 

  106. Ouwerkerk W, van den Berg M, van der Niet S et al (2019) Biomarkers, measured during therapy, for response of melanoma patients to immune checkpoint inhibitors: a systematic review. Melanoma Res 29:453–464. https://doi.org/10.1097/CMR.0000000000000589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tanaka A, Sakaguchi S (2017) Regulatory T cells in cancer immunotherapy. Cell Res 27:109–118. https://doi.org/10.1038/cr.2016.151

    Article  CAS  PubMed  Google Scholar 

  108. Hermans D, Gautam S, García-Cañaveras JC et al (2020) Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity. Proc Natl Acad Sci 117:6047–6055. https://doi.org/10.1073/pnas.1920413117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang Y, Kurupati R, Liu L et al (2017) Enhancing CD8+ T Cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32:377-391.e9. https://doi.org/10.1016/j.ccell.2017.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Menk AV, Scharping NE, Rivadeneira DB et al (2018) 4–1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med 215:1091–1100. https://doi.org/10.1084/jem.20171068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Disha Rao, Fabienne Verburg, Daniel S. Peeper, Ruben Lacroix & Christian U. Blank

  2. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Christian U. Blank

  3. Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany

    Kathrin Renner

  4. Oncode Institute, Utrecht, The Netherlands

    Daniel S. Peeper

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  1. Disha Rao
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  2. Fabienne Verburg
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  3. Kathrin Renner
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  4. Daniel S. Peeper
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  5. Ruben Lacroix
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  6. Christian U. Blank
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Contributions

D.R, R.L and C.U.B conceptualised the idea for the manuscript. All authors contributed to the literature search. The first draft of the manuscript was written by D.R, F.V and R.L. All authors were involved in critical revision of the manuscript and approval of the final manuscript.

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Correspondence to Christian U. Blank.

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C.U.B declares the following potential COI: advisory roles for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, research funding from BMS, Novartis, NanoString, co-founder of Immagene B.V. D.S.P received research support from MSD and BMS and is co-founder, shareholder and advisor of Immagene B.V.

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Ruben Lacroix and Christian U Blank: shared last authors.

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Rao, D., Verburg, F., Renner, K. et al. Metabolic profiles of regulatory T cells in the tumour microenvironment. Cancer Immunol Immunother 70, 2417–2427 (2021). https://doi.org/10.1007/s00262-021-02881-z

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