Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment

Cancer Immunology, Immunotherapy (2021)Cite this article

Abstract

Metabolic dysregulation in the hypoxic tumor microenvironment (TME) is considered as a hallmark of solid tumors, leading to changes in biosynthetic pathways favoring onset, survival and proliferation of malignant cells. Within the TME, hypoxic milieu favors metabolic reprogramming of tumor cells, which subsequently affects biological properties of tumor-infiltrating immune cells. T regulatory cells (Tregs), including both circulating and tissue-resident cells, are particularly susceptible to hypoxic metabolic signaling that can reprogram their biological and physicochemical properties. Furthermore, metabolic reprogramming modifies Tregs to utilize alternative substrates and undergo a plethora of metabolic events to meet their energy demands. Major impact of this metabolic reprogramming can result in differentiation, survival, excessive secretion of immunosuppressive cytokines and proliferation of Tregs within the TME, which in turn dampen anti-tumor immune responses. Studies on fine-tuning of Treg metabolism are challenging due to heterogenicity of tissue-resident Tregs and their dynamic functions. In this review, we highlight tumor intrinsic and extrinsic factors, which can influence Treg metabolism in the hypoxic TME. Moreover, we focus on metabolic reprogramming of Tregs that could unveil potential regulatory networks favoring tumorigenesis/progression, and provide novel insights, including inhibitors against acetyl-coA carboxylase 1 and transforming growth factor beta into targeting Treg metabolism for therapeutic benefits.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. 1.

    Bredberg A (2011) Cancer: more of polygenic disease and less of multiple mutations? A quantitative viewpoint. Cancer 117(3):440–445. https://doi.org/10.1002/cncr.25440

    Article  PubMed  Google Scholar 

  2. 2.

    Du G, Liu Y, Li J, Liu W, Wang Y, Li H (2013) Hypothermic microenvironment plays a key role in tumor immune subversion. Int Immunopharmacol 17(2):245–253. https://doi.org/10.1016/j.intimp.2013.06.018

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    CAS  Article  Google Scholar 

  4. 4.

    Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27(45):5904–5912. https://doi.org/10.1038/onc.2008.271

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99(19):1441–1454. https://doi.org/10.1093/jnci/djm135

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Syed Khaja AS, Toor SM, El Salhat H, Ali BR, Elkord E (2017) Intratumoral FoxP3(+)Helios(+) regulatory T cells upregulating immunosuppressive molecules are expanded in human colorectal cancer. Front Immunol 8:619. https://doi.org/10.3389/fimmu.2017.00619

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Syed Khaja AS, Toor SM, El Salhat H, Faour I, Ul Haq N, Ali BR, Elkord E (2017) Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment. Oncotarget 8(20):33159–33171. https://doi.org/10.18632/oncotarget.16565

    Article  PubMed  Google Scholar 

  8. 8.

    Chaudhary B, Elkord E (2016) Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines Basel. https://doi.org/10.3390/vaccines4030028

  9. 9.

    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949. https://doi.org/10.1038/nm1093

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA, Gilks CB, Lal P, Zhang L, Coukos G (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475(7355):226–230. https://doi.org/10.1038/nature10169

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470(7335):548–553. https://doi.org/10.1038/nature09707

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Wei S, Kryczek I, Edwards RP, Zou L, Szeliga W, Banerjee M, Cost M, Cheng P, Chang A, Redman B, Herberman RB, Zou W (2007) Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res 67(15):7487–7494. https://doi.org/10.1158/0008-5472.CAN-07-0565

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169(5):2756–2761. https://doi.org/10.4049/jimmunol.169.5.2756

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380. https://doi.org/10.1200/JCO.2006.05.9584

    Article  PubMed  Google Scholar 

  15. 15.

    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 5:15179. https://doi.org/10.1038/srep15179

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Bauer CA, Kim EY, Marangoni F, Carrizosa E, Claudio NM, Mempel TR (2014) Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest 124(6):2425–2440. https://doi.org/10.1172/JCI66375

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K (2018) Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8(+) T cells in the tumor microenvironment. J Immunother Cancer 6(1):106. https://doi.org/10.1186/s40425-018-0403-1

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Phan LM, Yeung SC, Lee MH (2014) Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med 11(1):1–19. https://doi.org/10.7497/j.issn.2095-3941.2014.01.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Hope HC, Salmond RJ (2019) Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy. Eur J Immunol 49(8):1147–1152. https://doi.org/10.1002/eji.201848058

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153(6):1239–1251. https://doi.org/10.1016/j.cell.2013.05.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR, Sendor AB, Chiang YJ, Corona AL, Gemta LF, Vincent BG, Wang RC, Kim B, Hong J, Chen CL, Bullock TN, Irish JM, Rathmell WK, Rathmell JC (2017) Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. https://doi.org/10.1172/jci.insight.93411

  22. 22.

    Kouidhi S, Elgaaied AB, Chouaib S (2017) Impact of metabolism on T-cell differentiation and function and cross talk with tumor microenvironment. Front Immunol 8:270. https://doi.org/10.3389/fimmu.2017.00270

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530. https://doi.org/10.1085/jgp.8.6.519

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38(9):2412–2418. https://doi.org/10.1002/eji.200838318

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Neildez-Nguyen TMA, Bigot J, Da Rocha S, Corre G, Boisgerault F, Paldi A, Galy A (2015) Hypoxic culture conditions enhance the generation of regulatory T cells. Immunology 144(3):431–443. https://doi.org/10.1111/imm.12388

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Guillaumond F, Leca J, Olivares O, Lavaut MN, Vidal N, Berthezene P, Dusetti NJ, Loncle C, Calvo E, Turrini O, Iovanna JL, Tomasini R, Vasseur S (2013) Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A 110(10):3919–3924. https://doi.org/10.1073/pnas.1219555110

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109(9):3812–3819. https://doi.org/10.1182/blood-2006-07-035972

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA, Mueller-Klieser W (2011) Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol 39(2):453–463. https://doi.org/10.3892/ijo.2011.1055

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513(7519):559–563. https://doi.org/10.1038/nature13490

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Constant JS, Feng JJ, Zabel DD, Yuan H, Suh DY, Scheuenstuhl H, Hunt TK, Hussain MZ (2000) Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair Regen 8(5):353–360. https://doi.org/10.1111/j.1524-475x.2000.00353.x

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Stern R, Shuster S, Neudecker BA, Formby B (2002) Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 276(1):24–31. https://doi.org/10.1006/excr.2002.5508

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Zhang JZ, Behrooz A, Ismail-Beigi F (1999) Regulation of glucose transport by hypoxia. Am J Kidney Dis 34(1):189–202. https://doi.org/10.1016/s0272-6386(99)70131-9

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Nagao A, Kobayashi M, Koyasu S, Chow CCT, Harada H (2019) HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int J Mol Sci. https://doi.org/10.3390/ijms20020238

  35. 35.

    Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davis W, Xu X, Karakousis GC, Schuchter LM, Xu W, Amaravadi R, Xiao M, Sadek N, Krepler C, Herlyn M, Freeman GJ, Rabinowitz JD, Ertl HCJ (2017) Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32(3):377–391 e379. https://doi.org/10.1016/j.ccell.2017.08.004

  36. 36.

    Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, Zhang P, Panek WK, Cordero A, Han Y, Ahmed AU, Chandel NS, Lesniak MS (2019) HIF-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep 27(1):226–237 e224. https://doi.org/10.1016/j.celrep.2019.03.029

  37. 37.

    Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186(6):3299–3303. https://doi.org/10.4049/jimmunol.1003613

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154. https://doi.org/10.1172/JCI31178

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9(10):1069–1077. https://doi.org/10.1038/sj.cdd.4401073

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761. https://doi.org/10.4049/jimmunol.176.11.6752

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N (2020) Regulatory T cells and human disease. Annu Rev Immunol 38:541–566. https://doi.org/10.1146/annurev-immunol-042718-041717

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Nishikawa H, Sakaguchi S (2014) Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 27:1–7. https://doi.org/10.1016/j.coi.2013.12.005

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. https://doi.org/10.1038/nrc3245

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911. https://doi.org/10.1016/j.immuni.2009.03.019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, Nagase H, Nishimura J, Yamamoto H, Takiguchi S, Tanoue T, Suda W, Morita H, Hattori M, Honda K, Mori M, Doki Y, Sakaguchi S (2016) Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 22(6):679–684. https://doi.org/10.1038/nm.4086

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ohue Y, Nishikawa H (2019) Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci 110(7):2080–2089. https://doi.org/10.1111/cas.14069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Seo N, Hayakawa S, Takigawa M, Tokura Y (2001) Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology 103(4):449–457. https://doi.org/10.1046/j.1365-2567.2001.01279.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, Drake CG, Powell JD (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111(1):251–259. https://doi.org/10.1182/blood-2007-03-081646

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30(5):626–635. https://doi.org/10.1016/j.immuni.2009.05.002

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, Pasca di Magliano M (2020) Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov 10(3):422–439. https://doi.org/10.1158/2159-8290.CD-19-0958

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, Chudakov DM, Rudensky AY (2016) Regulatory t cells exhibit distinct features in human breast cancer. Immunity 45(5):1122–1134. https://doi.org/10.1016/j.immuni.2016.10.032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Toor SM, Murshed K, Al-Dhaheri M, Khawar M, Abu Nada M, Elkord E (2019) Immune checkpoints in circulating and tumor-infiltrating CD4(+) T cell subsets in colorectal cancer patients. Front Immunol 10:2936. https://doi.org/10.3389/fimmu.2019.02936

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA (2009) Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 9(4):447–453. https://doi.org/10.1016/j.coph.2009.04.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13(18 Pt 1):5262–5270. https://doi.org/10.1158/1078-0432.CCR-07-1157

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Mirlekar B, Michaud D, Searcy R, Greene K, Pylayeva-Gupta Y (2018) IL35 hinders endogenous antitumor T-cell immunity and responsiveness to immunotherapy in pancreatic cancer. Cancer Immunol Res 6(9):1014–1024. https://doi.org/10.1158/2326-6066.CIR-17-0710

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310. https://doi.org/10.1084/jem.192.2.303

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Buchbinder EI, Desai A (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 39(1):98–106. https://doi.org/10.1097/COC.0000000000000239

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA (2004) Role of LAG-3 in regulatory T cells. Immunity 21(4):503–513. https://doi.org/10.1016/j.immuni.2004.08.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Campos-Mora M, Morales RA, Gajardo T, Catalan D, Pino-Lagos K (2013) Neuropilin-1 in transplantation tolerance. Front Immunol 4:405. https://doi.org/10.3389/fimmu.2013.00405

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Chaudhary B, Khaled YS, Ammori BJ, Elkord E (2014) Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother 63(2):81–99. https://doi.org/10.1007/s00262-013-1500-0

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ (2007) Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27(4):635–646. https://doi.org/10.1016/j.immuni.2007.08.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72(9):2162–2171. https://doi.org/10.1158/0008-5472.CAN-11-3687

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Katsuno Y, Lamouille S, Derynck R (2013) TGF-beta signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol 25(1):76–84. https://doi.org/10.1097/CCO.0b013e32835b6371

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Nickerson NK, Mill CP, Wu HJ, Riese DJ 2nd, Foley J (2013) Autocrine-derived epidermal growth factor receptor ligands contribute to recruitment of tumor-associated macrophage and growth of basal breast cancer cells in vivo. Oncol Res 20(7):303–317. https://doi.org/10.3727/096504013x13639794277761

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Paluskievicz CM, Cao X, Abdi R, Zheng P, Liu Y, Bromberg JS (2019) T regulatory cells and priming the suppressive tumor microenvironment. Front Immunol 10:2453. https://doi.org/10.3389/fimmu.2019.02453

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Gupta S, Joshi K, Wig JD, Arora SK (2007) Intratumoral FOXP3 expression in infiltrating breast carcinoma: its association with clinicopathologic parameters and angiogenesis. Acta Oncol 46(6):792–797. https://doi.org/10.1080/02841860701233443

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163(10):5211–5218

    CAS  PubMed  Google Scholar 

  68. 68.

    Shi C, Chen Y, Chen Y, Yang Y, Bing W, Qi J (2019) CD4(+) CD25(+) regulatory T cells promote hepatocellular carcinoma invasion via TGF-beta1-induced epithelial-mesenchymal transition. Onco Targets Ther 12:279–289. https://doi.org/10.2147/OTT.S172417

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ, 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293 e1287. https://doi.org/10.1016/j.cmet.2016.12.018

  70. 70.

    Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM (2017) Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47(5):875–889 e810. https://doi.org/10.1016/j.immuni.2017.10.017

  71. 71.

    Jordan JT, Sun W, Hussain SF, DeAngulo G, Prabhu SS, Heimberger AB (2008) Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother 57(1):123–131. https://doi.org/10.1007/s00262-007-0336-x

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Gobel G, Margreiter R, Konigsrainer A, Fuchs D, Amberger A (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12(4):1144–1151. https://doi.org/10.1158/1078-0432.CCR-05-1966

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Ino K, Yamamoto E, Shibata K, Kajiyama H, Yoshida N, Terauchi M, Nawa A, Nagasaka T, Takikawa O, Kikkawa F (2008) Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 14(8):2310–2317. https://doi.org/10.1158/1078-0432.CCR-07-4144

    CAS  Article  Google Scholar 

  74. 74.

    Nakamura T, Shima T, Saeki A, Hidaka T, Nakashima A, Takikawa O, Saito S (2007) Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci 98(6):874–881. https://doi.org/10.1111/j.1349-7006.2007.00470.x

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Folgiero V, Miele E, Carai A, Ferretti E, Alfano V, Po A, Bertaina V, Goffredo BM, Benedetti MC, Camassei FD, Cacchione A, Locatelli F, Mastronuzzi A (2016) IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma. Oncotarget 7(33):52900–52911. https://doi.org/10.18632/oncotarget.9284

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E, Faicchia D, Severa M, Rizzo F, Coccia EM, Bonacina F, Mitro N, Norata GD, Rossetti G, Ranzani V, Pagani M, Giorda E, Wei Y, Matarese G, Barnaba V, Piconese S (2018) Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci U S A 115(28):E6546-e6555. https://doi.org/10.1073/pnas.1720113115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, Gao A, Huang L, Hsueh EC, Ford DA, Hoft DF, Peng G (2019) TLR8-mediated metabolic control of human treg function: a mechanistic target for cancer immunotherapy. Cell Metab 29(1):103–123 e105. https://doi.org/10.1016/j.cmet.2018.09.020

  78. 78.

    Sun IH, Oh MH, Zhao L, Patel CH, Arwood ML, Xu W, Tam AJ, Blosser RL, Wen J, Powell JD (2018) mTOR complex 1 signaling regulates the generation and function of central and effector Foxp3(+) regulatory T Cells. J Immunol 201(2):481–492. https://doi.org/10.4049/jimmunol.1701477

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Lowe MM, Boothby I, Clancy S, Ahn RS, Liao W, Nguyen DN, Schumann K, Marson A, Mahuron KM, Kingsbury GA, Liu Z, Munoz Sandoval P, Rodriguez RS, Pauli ML, Taravati K, Arron ST, Neuhaus IM, Harris HW, Kim EA, Shin US, Krummel MF, Daud A, Scharschmidt TC, Rosenblum MD (2019) Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. https://doi.org/10.1172/jci.insight.129756

  80. 80.

    Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, Zhao L, Vatan L, Shao I, Szeliga W, Lyssiotis C, Liu JR, Kryczek I, Zou W (2017) Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 18(12):1332–1341. https://doi.org/10.1038/ni.3868

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, Hippen KL, Loschi M, Thangavelu G, Corrado M, Edwards-Hicks J, Grzes KM, Pearce EJ, Blazar BR, Pearce EL (2020) Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for treg suppressive function. Cell Metab 31(2):422–437 e425. https://doi.org/10.1016/j.cmet.2019.11.021

  82. 82.

    Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM, Martinez-Reyes I, Gao P, Helmin KA, Abdala-Valencia H, Sena LA, Schumacker PT, Turka LA, Chandel NS (2019) Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565(7740):495–499. https://doi.org/10.1038/s41586-018-0846-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Chang WH, Lai AG (2019) The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia. Ann N Y Acad Sci 1448(1):65–82. https://doi.org/10.1111/nyas.14170

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Muroski ME, Miska J, Chang AL, Zhang P, Rashidi A, Moore H, Lopez-Rosas A, Han Y, Lesniak MS (2017) Fatty acid uptake in T cell subsets using a quantum dot fatty acid conjugate. Sci Rep 7(1):5790. https://doi.org/10.1038/s41598-017-05556-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256. https://doi.org/10.1038/nature12428

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Magnuson AM, Kiner E, Ergun A, Park JS, Asinovski N, Ortiz-Lopez A, Kilcoyne A, Paoluzzi-Tomada E, Weissleder R, Mathis D, Benoist C (2018) Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. Proc Natl Acad Sci U S A 115(45):E10672–E10681. https://doi.org/10.1073/pnas.1810580115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Chapman NM, Zeng H, Nguyen TM, Wang Y, Vogel P, Dhungana Y, Liu X, Neale G, Locasale JW, Chi H (2018) mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat Commun 9(1):2095. https://doi.org/10.1038/s41467-018-04392-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Donninelli G, Del Corno M, Pierdominici M, Scazzocchio B, Vari R, Varano B, Pacella I, Piconese S, Barnaba V, D’Archivio M, Masella R, Conti L, Gessani S (2017) Distinct blood and visceral adipose tissue regulatory T cell and innate lymphocyte profiles characterize obesity and colorectal cancer. Front Immunol 8:643. https://doi.org/10.3389/fimmu.2017.00643

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Raychaudhuri D, Bhattacharya R, Sinha BP, Liu CSC, Ghosh AR, Rahaman O, Bandopadhyay P, Sarif J, D’Rozario R, Paul S, Das A, Sarkar DK, Chattopadhyay S, Ganguly D (2019) Lactate induces pro-tumor reprogramming in intratumoral plasmacytoid dendritic cells. Front Immunol 10:1878. https://doi.org/10.3389/fimmu.2019.01878

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E, Greenson J, Chang A, Rolinski J, Radwan P, Fang J, Wang G, Zou W (2011) IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol 186(7):4388–4395. https://doi.org/10.4049/jimmunol.1003251

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Rizzo A, Di Giovangiulio M, Stolfi C, Franze E, Fehling HJ, Carsetti R, Giorda E, Colantoni A, Ortenzi A, Rugge M, Mescoli C, Monteleone G, Fantini MC (2018) RORgammat-expressing tregs drive the growth of colitis-associated colorectal cancer by controlling IL6 in dendritic cells. Cancer Immunol Res 6(9):1082–1092. https://doi.org/10.1158/2326-6066.CIR-17-0698

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Jetten AM, Takeda Y, Slominski A, Kang HS (2018) Retinoic acid-related orphan receptor gamma (RORgamma): connecting sterol metabolism to regulation of the immune system and autoimmune disease. Curr Opin Toxicol 8:66–80. https://doi.org/10.1016/j.cotox.2018.01.005

    Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Pan Y, Tian T, Park CO, Lofftus SY, Mei S, Liu X, Luo C, O’Malley JT, Gehad A, Teague JE, Divito SJ, Fuhlbrigge R, Puigserver P, Krueger JG, Hotamisligil GS, Clark RA, Kupper TS (2017) Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543(7644):252–256. https://doi.org/10.1038/nature21379

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Kabelitz D, Wesch D, He W (2007) Perspectives of gammadelta T cells in tumor immunology. Cancer Res 67(1):5–8. https://doi.org/10.1158/0008-5472.CAN-06-3069

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF (2007) Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity 27(2):334–348. https://doi.org/10.1016/j.immuni.2007.05.020

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Wesch D, Peters C, Siegers GM (2014) Human gamma delta T regulatory cells in cancer: fact or fiction? Front Immunol 5:598. https://doi.org/10.3389/fimmu.2014.00598

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Kang N, Tang L, Li X, Wu D, Li W, Chen X, Cui L, Ba D, He W (2009) Identification and characterization of Foxp3(+) gammadelta T cells in mouse and human. Immunol Lett 125(2):105–113. https://doi.org/10.1016/j.imlet.2009.06.005

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Wevers E, Schwartz T, Hunborg P, Varvares MA, Hoft DF, Hsueh EC, Peng G (2012) Tumor-infiltrating gammadelta T lymphocytes predict clinical outcome in human breast cancer. J Immunol 189(10):5029–5036. https://doi.org/10.4049/jimmunol.1201892

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G (2003) Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197(2):163–168. https://doi.org/10.1084/jem.20021500

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Raverdeau M, Cunningham SP, Harmon C, Lynch L (2019) gammadelta T cells in cancer: a small population of lymphocytes with big implications. Clin Transl Immunol 8(10):e01080. https://doi.org/10.1002/cti2.1080

    Article  Google Scholar 

  101. 101.

    Wang H, Henry O, Distefano MD, Wang YC, Raikkonen J, Monkkonen J, Tanaka Y, Morita CT (2013) Butyrophilin 3A1 plays an essential role in prenyl pyrophosphate stimulation of human Vgamma2Vdelta2 T cells. J Immunol 191(3):1029–1042. https://doi.org/10.4049/jimmunol.1300658

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Casetti R, Agrati C, Wallace M, Sacchi A, Martini F, Martino A, Rinaldi A, Malkovsky M (2009) Cutting edge: TGF-beta1 and IL-15 Induce FOXP3+ gammadelta regulatory T cells in the presence of antigen stimulation. J Immunol 183(6):3574–3577. https://doi.org/10.4049/jimmunol.0901334

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Schreiber TH, Wolf D, Bodero M, Podack E (2012) Tumor antigen specific iTreg accumulate in the tumor microenvironment and suppress therapeutic vaccination. Oncoimmunology 1(5):642–648. https://doi.org/10.4161/onci.20298

    Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Zhou G, Drake CG, Levitsky HI (2006) Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107(2):628–636. https://doi.org/10.1182/blood-2005-07-2737

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK (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 U S A 109(41):E2784-2793. https://doi.org/10.1073/pnas.1202366109

    Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Fong GH, Takeda K (2008) Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ 15(4):635–641. https://doi.org/10.1038/cdd.2008.10

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Deng B, Zhu JM, Wang Y, Liu TT, Ding YB, Xiao WM, Lu GT, Bo P, Shen XZ (2013) Intratumor hypoxia promotes immune tolerance by inducing regulatory T cells via TGF-beta1 in gastric cancer. PLoS ONE 8(5):e63777. https://doi.org/10.1371/journal.pone.0063777

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Chen J, Jiang CC, Jin L, Zhang XD (2016) Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 27(3):409–416. https://doi.org/10.1093/annonc/mdv615

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Ruf M, Moch H, Schraml P (2016) PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer 139(2):396–403. https://doi.org/10.1002/ijc.30077

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL (2010) Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE 5(7):e11469. https://doi.org/10.1371/journal.pone.0011469

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J, Wang Z, Chen X, Zhang W, Yokoyama S, Wang C, Li L, Li L, Hou D, Dong L, Xu T, Hiroi T, Yang F, Ji H, Zhang J, Zen K, Zhang CY (2014) Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res 24(10):1164–1180. https://doi.org/10.1038/cr.2014.121

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA (1997) Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7(5):679–689. https://doi.org/10.1016/s1074-7613(00)80388-x

    CAS  Article  PubMed  Google Scholar 

  113. 113.

    Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16(2):188–196. https://doi.org/10.1038/ni.3077

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Haxhinasto S, Mathis D, Benoist C (2008) The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 205(3):565–574. https://doi.org/10.1084/jem.20071477

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376. https://doi.org/10.1084/jem.20110278

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20(11):1327–1333. https://doi.org/10.1038/nm.3704

    CAS  Article  Google Scholar 

  117. 117.

    Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, Lombardo PS, Van Nostrand JL, Hutchins A, Vera L, Gerken L, Greenwood J, Bhat S, Harriman G, Westlin WF, Harwood HJ Jr, Saghatelian A, Kapeller R, Metallo CM, Shaw RJ (2016) Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 22(10):1108–1119. https://doi.org/10.1038/nm.4181

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, Warmoes MO, de Cubas AA, MacIver NJ, Locasale JW, Turka LA, Wells AD, Rathmell JC (2016) Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol 17(12):1459–1466. https://doi.org/10.1038/ni.3577

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Procaccini C, De Rosa V, Galgani M, Abanni L, Cali G, Porcellini A, Carbone F, Fontana S, Horvath TL, La Cava A, Matarese G (2010) An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33(6):929–941. https://doi.org/10.1016/j.immuni.2010.11.024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Hosomi K, Kunisawa J (2017) The specific roles of vitamins in the regulation of immunosurveillance and maintenance of immunologic homeostasis in the gut. Immune Netw 17(1):13–19. https://doi.org/10.4110/in.2017.17.1.13

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Lu L, Lan Q, Li Z, Zhou X, Gu J, Li Q, Wang J, Chen M, Liu Y, Shen Y, Brand DD, Ryffel B, Horwitz DA, Quismorio FP, Liu Z, Li B, Olsen NJ, Zheng SG (2014) Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A 111(33):E3432-3440. https://doi.org/10.1073/pnas.1408780111

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Lu L, Ma J, Li Z, Lan Q, Chen M, Liu Y, Xia Z, Wang J, Han Y, Shi W, Quesniaux V, Ryffel B, Brand D, Li B, Liu Z, Zheng SG (2011) All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus. PLoS ONE 6(9):e24590. https://doi.org/10.1371/journal.pone.0024590

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Sci NY 317(5835):256–260. https://doi.org/10.1126/science.1145697

    CAS  Article  Google Scholar 

  124. 124.

    Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA (2007) IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 178(4):2018–2027. https://doi.org/10.4049/jimmunol.178.4.2018

    CAS  Article  PubMed  Google Scholar 

  125. 125.

    Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D, Benoist C (2008) Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity 29(5):758–770. https://doi.org/10.1016/j.immuni.2008.09.018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Yue X, Trifari S, Äijö T, Tsagaratou A, Pastor WA, Zepeda-Martínez JA, Lio CW, Li X, Huang Y, Vijayanand P, Lähdesmäki H, Rao A (2016) Control of Foxp3 stability through modulation of TET activity. J Exp Med 213(3):377–397. https://doi.org/10.1084/jem.20151438

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Sasidharan Nair V, Song MH, Oh KI (2016) Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J Immunol 196(5):2119–2131. https://doi.org/10.4049/jimmunol.1502352

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30(7):733–750. https://doi.org/10.1101/gad.276568.115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Yue X, Lio CJ, Samaniego-Castruita D, Li X, Rao A (2019) Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nat Commun 10(1):2011. https://doi.org/10.1038/s41467-019-09541-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Nikolouli E, Hardtke-Wolenski M, Hapke M, Beckstette M, Geffers R, Floess S, Jaeckel E, Huehn J (2017) Alloantigen-induced regulatory T cells generated in presence of vitamin C display enhanced stability of Foxp3 expression and promote skin allograft acceptance. Front Immunol 8:748. https://doi.org/10.3389/fimmu.2017.00748

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183(9):5458–5467. https://doi.org/10.4049/jimmunol.0803217

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan C, Ichiyama K, Yoshimura A, Steinman L, Christakos S, Youssef S (2011) 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 31(17):3653–3669. https://doi.org/10.1128/mcb.05020-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS, Lee SH, Kim WU, Kang I (2012) 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol 188(11):5276–5282. https://doi.org/10.4049/jimmunol.1101211

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Fisher SA, Rahimzadeh M, Brierley C, Gration B, Doree C, Kimber CE, Plaza Cajide A, Lamikanra AA, Roberts DJ (2019) The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: a systematic review. PLoS ONE 14(9):e0222313. https://doi.org/10.1371/journal.pone.0222313

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40(1):128–139. https://doi.org/10.1016/j.immuni.2013.12.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Hegyi J, Schwartz RA, Hegyi V (2004) Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol 43(1):1–5. https://doi.org/10.1111/j.1365-4632.2004.01959.x

    Article  PubMed  Google Scholar 

  137. 137.

    Moretti S, Menicali E, Voce P, Morelli S, Cantarelli S, Sponziello M, Colella R, Fallarino F, Orabona C, Alunno A, de Biase D, Bini V, Mameli MG, Filetti S, Gerli R, Macchiarulo A, Melillo RM, Tallini G, Santoro M, Puccetti P, Avenia N, Puxeddu E (2014) Indoleamine 2,3-dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment. J Clin Endocrinol Metabol 99(5):E832-840. https://doi.org/10.1210/jc.2013-3351

    CAS  Article  Google Scholar 

  138. 138.

    Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183(4):2475–2483. https://doi.org/10.4049/jimmunol.0900986

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y, Munn DH (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113(24):6102–6111. https://doi.org/10.1182/blood-2008-12-195354

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117(9):2570–2582. https://doi.org/10.1172/jci31911

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203. https://doi.org/10.1038/nature10491

    CAS  Article  PubMed  Google Scholar 

  142. 142.

    Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A 107(46):19961–19966. https://doi.org/10.1073/pnas.1014465107

    Article  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22(5):633–642. https://doi.org/10.1016/j.immuni.2005.03.013

    CAS  Article  PubMed  Google Scholar 

  144. 144.

    Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, Powell JD, Yagita H, Mellor AL, Blazar BR, Munn DH (2015) The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv 1(10):e1500845. https://doi.org/10.1126/sciadv.1500845

    Article  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F (2011) ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal 4(162):ra12. https://doi.org/10.1126/scisignal.2001270

  146. 146.

    Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4):1225–1232. https://doi.org/10.1182/blood-2006-12-064527

    CAS  Article  PubMed  Google Scholar 

  147. 147.

    Saleh R, Elkord E (2020) FoxP3(+) T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett 490:174–185. https://doi.org/10.1016/j.canlet.2020.07.022

    CAS  Article  PubMed  Google Scholar 

  148. 148.

    Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265. https://doi.org/10.1084/jem.20062512

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Saleh R, Elkord E (2019) Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett 457:168–179. https://doi.org/10.1016/j.canlet.2019.05.003

    CAS  Article  PubMed  Google Scholar 

  150. 150.

    Li JY, Duan XF, Wang LP, Xu YJ, Huang L, Zhang TF, Liu JY, Li F, Zhang Z, Yue DL, Wang F, Zhang B, Zhang Y (2014) Selective depletion of regulatory T cell subsets by docetaxel treatment in patients with nonsmall cell lung cancer. J Immunol Res 2014:286170. https://doi.org/10.1155/2014/286170

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Lissoni P, Brivio F, Fumagalli L, Messina G, Meregalli S, Porro G, Rovelli F, Vigorè L, Tisi E, D’Amico G (2009) Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res 29(5):1847–1852

    CAS  PubMed  Google Scholar 

  152. 152.

    Verma A, Mathur R, Farooque A, Kaul V, Gupta S, Dwarakanath BS (2019) T-regulatory cells in tumor progression and therapy. Cancer Manag Res 11:10731–10747. https://doi.org/10.2147/CMAR.S228887

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Cao M, Cabrera R, Xu Y, Liu C, Nelson D (2009) Gamma irradiation alters the phenotype and function of CD4+CD25+ regulatory T cells. Cell Biol Int 33(5):565–571. https://doi.org/10.1016/j.cellbi.2009.02.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Greten TF, Ormandy LA, Fikuart A, Höchst B, Henschen S, Hörning M, Manns MP, Korangy F (2010) Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother (Hagerstown, Md : 1997) 33(2):211–218. https://doi.org/10.1097/CJI.0b013e3181bb499f

  155. 155.

    Generali D, Bates G, Berruti A, Brizzi MP, Campo L, Bonardi S, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Banham AH, Harris AL, Bottini A, Fox SB (2009) Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin Cancer Res 15(3):1046–1051. https://doi.org/10.1158/1078-0432.ccr-08-1507

    CAS  Article  PubMed  Google Scholar 

  156. 156.

    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(10):1273–1280. https://doi.org/10.1002/stem.3051

    Article  PubMed  Google Scholar 

  157. 157.

    Patel MA, Kim JE, Theodros D, Tam A, Velarde E, Kochel CM, Francica B, Nirschl TR, Ghasemzadeh A, Mathios D, Harris-Bookman S, Jackson CC, Jackson C, Ye X, Tran PT, Tyler B, Coric V, Selby M, Brem H, Drake CG, Pardoll DM, Lim M (2016) Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. J Immunother Cancer 4:28. https://doi.org/10.1186/s40425-016-0132-2

    Article  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Muroyama Y, Nirschl TR, Kochel CM, Lopez-Bujanda Z, Theodros D, Mao W, Carrera-Haro MA, Ghasemzadeh A, Marciscano AE, Velarde E, Tam AJ, Thoburn CJ, Uddin M, Meeker AK, Anders RA, Pardoll DM, Drake CG (2017) Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol Res 5(11):992–1004. https://doi.org/10.1158/2326-6066.cir-17-0040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Schuler PJ, Harasymczuk M, Schilling B, Saze Z, Strauss L, Lang S, Johnson JT, Whiteside TL (2013) Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer. Clin Cancer Res 19(23):6585–6596. https://doi.org/10.1158/1078-0432.CCR-13-0900

    CAS  Article  PubMed  Google Scholar 

  160. 160.

    Oweida A, Darragh L, Bhatia S, Raben D, Heasley L, Nemenoff R, Clambey E, Karam S (2019) Regulatory T cells mediate resistance to radiotherapy in head and neck squamous cell carcinoma. J Clin Oncol 37(8_suppl):70–70. https://doi.org/10.1200/JCO.2019.37.8_suppl.70

  161. 161.

    Crellin NK, Garcia RV, Levings MK (2007) Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 109(5):2014–2022. https://doi.org/10.1182/blood-2006-07-035279

    CAS  Article  PubMed  Google Scholar 

  162. 162.

    Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM, Fisher AG, Merkenschlager M (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 105(22):7797–7802. https://doi.org/10.1073/pnas.0800928105

    Article  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490. https://doi.org/10.1038/nature12297

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A (2018) Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. Int Immunol 30(8):357–373. https://doi.org/10.1093/intimm/dxy043

    CAS  Article  PubMed  Google Scholar 

  165. 165.

    Basu S, Hubbard B, Shevach EM (2015) Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells. J Leukoc Biol 97(2):279–283. https://doi.org/10.1189/jlb.2AB0514-273RR

    CAS  Article  PubMed  Google Scholar 

  166. 166.

    Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16(2):178–187. https://doi.org/10.1038/ni.3076

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029. https://doi.org/10.1084/jem.20090847

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA (2012) Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 5(230):ra46. https://doi.org/10.1126/scisignal.2002796

  169. 169.

    Gottschalk RA, Corse E, Allison JP (2010) TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J Exp Med 207(8):1701–1711. https://doi.org/10.1084/jem.20091999

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Li MO, Rudensky AY (2016) T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat Rev Immunol 16(4):220–233. https://doi.org/10.1038/nri.2016.26

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171.

    O’Connor RS, Guo L, Ghassemi S, Snyder NW, Worth AJ, Weng L, Kam Y, Philipson B, Trefely S, Nunez-Cruz S, Blair IA, June CH, Milone MC (2018) The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci Rep 8(1):6289. https://doi.org/10.1038/s41598-018-24676-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V, Zuercher WJ, Powell JD, Shinohara ML, McDonnell DP, Rathmell JC (2011) Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A 108(45):18348–18353. https://doi.org/10.1073/pnas.1108856108

    Article  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. https://doi.org/10.1016/j.cell.2011.07.033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Feldhoff LM, Rueda CM, Moreno-Fernandez ME, Sauer J, Jackson CM, Chougnet CA, Rupp J (2017) IL-1β induced HIF-1α inhibits the differentiation of human FOXP3(+) T cells. Sci Rep 7(1):465. https://doi.org/10.1038/s41598-017-00508-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, Palmer DC, Phan AT, Goulding J, Gattinoni L, Goldrath AW, Belkaid Y, Restifo NP (2016) Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166(5):1117-1131.e1114. https://doi.org/10.1016/j.cell.2016.07.032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Lee JH, Elly C, Park Y, Liu YC (2015) E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T Cell stability and suppressive capacity. Immunity 42(6):1062–1074. https://doi.org/10.1016/j.immuni.2015.05.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood JM, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA (2017) Interferon-γ drives T(reg) fragility to promote anti-tumor immunity. Cell 169(6):1130-1141.e1111. https://doi.org/10.1016/j.cell.2017.05.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. 178.

    He N, Fan W, Henriquez B, Yu RT, Atkins AR, Liddle C, Zheng Y, Downes M, Evans RM (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A 114(47):12542–12547. https://doi.org/10.1073/pnas.1715363114

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Rotin D, Robinson B, Tannock IF (1986) Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors. Cancer Res 46(6):2821–2826

    CAS  PubMed  Google Scholar 

  180. 180.

    Spill F, Reynolds DS, Kamm RD, Zaman MH (2016) Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol 40:41–48. https://doi.org/10.1016/j.copbio.2016.02.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Chaudhuri O, Koshy ST, Branco da Cunha C, Shin JW, Verbeke CS, Allison KH, Mooney DJ (2014) Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat Mater 13(10):970–978. https://doi.org/10.1038/nmat4009

    CAS  Article  PubMed  Google Scholar 

  182. 182.

    Bollyky PL, Falk BA, Wu RP, Buckner JH, Wight TN, Nepom GT (2009) Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells. J Leukoc Biol 86(3):567–572. https://doi.org/10.1189/jlb.0109001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. 183.

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

    Article  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Schurich A, Magalhaes I, Mattsson J (2019) Metabolic regulation of CAR T cell function by the hypoxic microenvironment in solid tumors. Immunotherapy 11(4):335–345. https://doi.org/10.2217/imt-2018-0141

    CAS  Article  PubMed  Google Scholar 

  185. 185.

    Yadav UP, Singh T, Kumar P, Sharma P, Kaur H, Sharma S, Singh S, Kumar S, Mehta K (2020) Metabolic adaptations in cancer stem cells. Front Oncol 10:1010. https://doi.org/10.3389/fonc.2020.01010

    Article  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Wang Y-A, Li X-L, Mo Y-Z, Fan C-M, Tang L, Xiong F, Guo C, Xiang B, Zhou M, Ma J, Huang X, Wu X, Li Y, Li G-Y, Zeng Z-Y, Xiong W (2018) Effects of tumor metabolic microenvironment on regulatory T cells. Mol Cancer 17(1):168. https://doi.org/10.1186/s12943-018-0913-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

  1. Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar

    Varun Sasidharan Nair, Reem Saleh & Salman M. Toor

  2. Department of Basic Medical Sciences, College of Medicine, Member of QU Health, Qatar University, Doha, Qatar

    Farhan S. Cyprian

  3. Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, M5 4WT, UK

    Eyad Elkord

Authors
  1. Varun Sasidharan Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reem Saleh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Salman M. Toor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Farhan S. Cyprian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eyad Elkord
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VN, RS and ST wrote the article and prepared figures/table. FC assisted in writing-review and editing. EE conceived the concept, acquired funds, supervised and performed writing-review and editing.

Corresponding author

Correspondence to Eyad Elkord.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sasidharan Nair, V., Saleh, R., Toor, S.M. et al. Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment. Cancer Immunol Immunother (2021). https://doi.org/10.1007/s00262-020-02842-y

Download citation

Keywords

  • T regulatory cells
  • Hypoxia
  • Tumor microenvironment
  • Metabolism
  • Glycolysis
  • Fatty acid metabolism