Metabolic and epigenetic regulation of T-cell exhaustion

Abstract

Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8+ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Features of T-cell exhaustion and epigenetic reprogramming.
Fig. 2: Environmental challenges skew T-cell differentiation and exhaustion.
Fig. 3: Cross-talk between metabolic alterations and epigenetic reprogramming in T-cell exhaustion.
Fig. 4: Roles of mitochondria and ER-related signalling in T-cell exhaustion.

References

  1. 1.

    Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015). Refs. 1 and 2 demonstrate that glucose deprivation suppresses T-cell antitumour immunity, which can be enhanced by metabolic reprogramming.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).

    CAS  PubMed  Google Scholar 

  4. 4.

    Bauer, D. E. et al. Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. FASEB J. 18, 1303–1305 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    PubMed  Google Scholar 

  8. 8.

    Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Alfei, F. & Zehn, D. T cell exhaustion: an epigenetically imprinted phenotypic and functional makeover. Trends Mol. Med. 23, 769–771 (2017). This article demonstrates that TOX is a critical transcription factor in the development and maintenance of exhausted T cells during chronic viral infection.

    CAS  PubMed  Google Scholar 

  11. 11.

    Baitsch, L. et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Odorizzi, P. M., Pauken, K. E., Paley, M. A., Sharpe, A. & Wherry, E. J. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J. Exp. Med. 212, 1125–1137 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e119 (2017). This article reveals that terminally exhausted T cells display a unique epigenetic landscape, which dampens T-cell effector functions and the efficacy of PD-1 blockade treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion council. Immunity 45, 358–373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Schurich, A. et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep. 16, 1243–1252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).

    CAS  PubMed  Google Scholar 

  19. 19.

    Sugiura, A. & Rathmell, J. C. Metabolic barriers to T cell function in tumors. J. Immunol. 200, 400–407 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Siska, P. J. et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2, e93411 (2017).

    PubMed Central  Google Scholar 

  21. 21.

    Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 701–703 (2016). This article provides evidence of the link between dysfunctional mitochondria and decreased antitumour immunity.

    CAS  PubMed  Google Scholar 

  22. 22.

    Ma, X. et al. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 30, 143–156.e145 (2019). This article shows that the ER-stress–XBP1 pathway drives T-cell exhaustion via cholesterol in the tumour microenvironment.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Cao, Y. et al. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat. Commun. 10, 1280 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    CAS  PubMed  Google Scholar 

  25. 25.

    Mueller, S. N. & Ahmed, R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 106, 8623–8628 (2009).

    CAS  PubMed  Google Scholar 

  26. 26.

    Utzschneider, D. T. et al. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. J. Exp. Med. 213, 1819–1834 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Angelosanto, J. M., Blackburn, S. D., Crawford, A. & Wherry, E. J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86, 8161–8170 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Sawant, D. V. et al. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat. Immunol. 20, 724–735 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Matloubian, M., Concepcion, R. J. & Ahmed, R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68, 8056–8063 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    CAS  Google Scholar 

  31. 31.

    Sharpe, A. H., Wherry, E. J., Ahmed, R. & Freeman, G. J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239–245 (2007).

    CAS  PubMed  Google Scholar 

  32. 32.

    Frebel, H. et al. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. J. Exp. Med. 209, 2485–2499 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Wang, C., Singer, M. & Anderson, A. C. Molecular dissection of CD8+ T-cell dysfunction. Trends Immunol. 38, 567–576 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).

    CAS  PubMed  Google Scholar 

  36. 36.

    Utzschneider, D. T. et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 14, 603–610 (2013).

    CAS  PubMed  Google Scholar 

  37. 37.

    Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016).

    CAS  PubMed  Google Scholar 

  39. 39.

    Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e110 (2019).

    CAS  PubMed  Google Scholar 

  40. 40.

    Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019). This article identifies a TCF1+ subpopulation of exhausted CD8+ TILs, denoted progenitor exhausted T cells, which are better able to control tumour growth with polyfunctionality and respond to anti-PD-1 treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Brummelman, J. et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. J. Exp. Med. 215, 2520–2535 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Chen, Z. et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 51, 840–855.e845 (2019).

    CAS  PubMed  Google Scholar 

  43. 43.

    Beltra, J. C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841.e828 (2020).

    CAS  PubMed  Google Scholar 

  44. 44.

    Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    CAS  PubMed  Google Scholar 

  45. 45.

    Nishikawa, H. & Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol. 27, 1–7 (2014).

    CAS  PubMed  Google Scholar 

  46. 46.

    Wang, H., Franco, F. & Ho, P. C. Metabolic regulation of tregs in cancer: opportunities for immunotherapy. Trends Cancer 3, 583–592 (2017).

    CAS  PubMed  Google Scholar 

  47. 47.

    Bates, G. J. et al. 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, 5373–5380 (2006).

    PubMed  Google Scholar 

  48. 48.

    Kim, Y. J., Park, S. J. & Broxmeyer, H. E. Phagocytosis, a potential mechanism for myeloid-derived suppressor cell regulation of CD8+ T cell function mediated through programmed cell death-1 and programmed cell death-1 ligand interaction. J. Immunol. 187, 2291–2301 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474–481 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ho, P. C. & Liu, P. S. Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. J. Immunother. Cancer 4, 4 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Li, X. et al. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat. Rev. Clin. Oncol. 16, 425–441 (2019).

    CAS  PubMed  Google Scholar 

  52. 52.

    Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Yan, Y. et al. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J. Immunol. 185, 5953–5961 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Rodriguez, P. C. et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 69, 1553–1560 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Speiser, D. E., Ho, P. C. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16, 599–611 (2016).

    CAS  PubMed  Google Scholar 

  56. 56.

    Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).

    CAS  PubMed  Google Scholar 

  57. 57.

    Metz, R. et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. OncoImmunology 1, 1460–1468 (2012).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

    CAS  PubMed  Google Scholar 

  59. 59.

    Das, A. et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111–2124 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210 (2019).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ma, E. H. et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 25, 345–357 (2017).

    CAS  PubMed  Google Scholar 

  62. 62.

    Staron, M. M. et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity 41, 802–814 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Angin, M. et al. Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection. Nat. Metab. 1, 704–716 (2019).

    CAS  PubMed  Google Scholar 

  64. 64.

    Barili, V. et al. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nat. Commun. 11, 604 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    MacKenzie, E. D. et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol. Cell. Biol. 27, 3282–3289 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Palazon, A. et al. An HIF-1alpha/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669–683.e665 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X. & Delgoffe, G. M. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol. Res. 5, 9–16 (2017).

    CAS  PubMed  Google Scholar 

  69. 69.

    Najjar, Y. G. et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI Insight 4, e124989 (2019).

    PubMed Central  Google Scholar 

  70. 70.

    Vuillefroy de Silly, R. et al. Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. Eur. J. Immunol. 45, 2263–2275 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    CAS  PubMed  Google Scholar 

  72. 72.

    Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    CAS  PubMed  Google Scholar 

  73. 73.

    Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Al-Khami, A. A. et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. OncoImmunology 6, e1344804 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 16, 880–886 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Niu, Z. et al. Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat. Commun. 8, 766 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Field, C. S. et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab. 31, 422–437.e425 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Zhang, Y. et al. Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32, 377–391.e379 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).

    CAS  PubMed  Google Scholar 

  84. 84.

    Singer, M. et al. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell 166, 1500–1511.e1509 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).

    CAS  PubMed  Google Scholar 

  87. 87.

    Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019).

    CAS  PubMed  Google Scholar 

  88. 88.

    Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).

    CAS  PubMed  Google Scholar 

  90. 90.

    Seo, H. et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc. Natl Acad. Sci. USA 116, 12410–12415 (2019).

    CAS  PubMed  Google Scholar 

  91. 91.

    Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Liu, X. et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature 567, 525–529 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Franchina, D. G., Dostert, C. & Brenner, D. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol. 39, 489–502 (2018).

    CAS  PubMed  Google Scholar 

  95. 95.

    Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018).

    CAS  PubMed  Google Scholar 

  98. 98.

    Bengsch, B. et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity 48, 1029–1045.e1025 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Larsen, G. A., Skjellegrind, H. K., Berg-Johnsen, J., Moe, M. C. & Vinje, M. L. Depolarization of mitochondria in isolated CA1 neurons during hypoxia, glucose deprivation and glutamate excitotoxicity. Brain Res. 1077, 153–160 (2006).

    CAS  PubMed  Google Scholar 

  100. 100.

    Almeida, A., Delgado-Esteban, M., Bolaños, J. P. & Medina, J. M. Oxygen and glucose deprivation induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture. J. Neurochem. 81, 207–217 (2002).

    CAS  PubMed  Google Scholar 

  101. 101.

    Kemp, K. & Poe, C. Stressed: the unfolded protein response in T cell development, activation, and function. Int. J. Mol. Sci. 20, 1792 (2019).

    CAS  PubMed Central  Google Scholar 

  102. 102.

    Kamimura, D. & Bevan, M. J. Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J. Immunol. 181, 5433–5441 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Song, M. et al. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562, 423–428 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Ogando, J. et al. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes. J. Immunother. Cancer 7, 151 (2019).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Li, C. et al. The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality. Immunity 51, 491–507.e497 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Chowdhury, P. S., Chamoto, K., Kumar, A. & Honjo, T. PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8+ T cells and facilitates anti-PD-1 therapy. Cancer Immunol. Res. 6, 1375–1387 (2018).

    CAS  PubMed  Google Scholar 

  108. 108.

    Menk, A. V. et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp. Med. 215, 1091–1100 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Teijeira, A. et al. Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation. Cancer Immunol. Res. 6, 798–811 (2018).

    CAS  PubMed  Google Scholar 

  110. 110.

    Ozcan, U. et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541–551 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Hurst, K. E. et al. Endoplasmic reticulum stress contributes to mitochondrial exhaustion of CD8+ T cells. Cancer Immunol. Res. 7, 476–486 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Lee, S. & Min, K. T. The interface between ER and mitochondria: molecular compositions and functions. Mol. Cells 41, 1000–1007 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Namgaladze, D., Khodzhaeva, V. & Brüne, B. ER-mitochondria communication in cells of the innate immune system. Cells 8, 1088 (2019).

    CAS  PubMed Central  Google Scholar 

  114. 114.

    Moltedo, O., Remondelli, P. & Amodio, G. The mitochondria-endoplasmic reticulum contacts and their critical role in aging and age-associated diseases. Front. Cell Dev. Biol. 7, 172 (2019).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Martinvalet, D. The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses. Cell Death Dis. 9, 336 (2018).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Bantug, G. R. et al. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 48, 542–555.e546 (2018). This article highlights the importance of mitochondria–ER interaction in immunometabolic regulation and recall response in memory CD8 T cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Boland, M. L., Chourasia, A. H. & Macleod, K. F. Mitochondrial dysfunction in cancer. Front. Oncol. 3, 292 (2013).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Quirós, P. M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).

    PubMed  Google Scholar 

  120. 120.

    Matilainen, O., Quirós, P. M. & Auwerx, J. Mitochondria and epigenetics: crosstalk in homeostasis and stress. Trends Cell Biol. 27, 453–463 (2017).

    CAS  PubMed  Google Scholar 

  121. 121.

    Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074.e2065 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Kuroda, S. et al. Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression. Proc. Natl Acad. Sci. USA 108, 14885–14889 (2011).

    CAS  PubMed  Google Scholar 

  124. 124.

    Chang, S. & Aune, T. M. Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat. Immunol. 8, 723–731 (2007).

    CAS  PubMed  Google Scholar 

  125. 125.

    Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).

    CAS  PubMed  Google Scholar 

  129. 129.

    Nabe, S. et al. Reinforce the antitumor activity of CD8+ T cells via glutamine restriction. Cancer Sci. 109, 3737–3750 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Suzuki, J. et al. The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation. Nat. Commun. 9, 3296 (2018).

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).

    PubMed  Google Scholar 

  133. 133.

    Ye, C. & Tu, B. P. Sink into the epigenome: histones as repositories that influence cellular metabolism. Trends Endocrinol. Metab. 29, 626–637 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Koyama, S. et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 7, 10501 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Kakavand, H. et al. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod. Pathol. 30, 1666–1676 (2017).

    CAS  PubMed  Google Scholar 

  138. 138.

    Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Kim, J. E. et al. Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin. Cancer Res. 23, 124–136 (2017).

    CAS  PubMed  Google Scholar 

  141. 141.

    Zhou, G. et al. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. OncoImmunology 7, e1448332 (2018).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016).

    CAS  PubMed  Google Scholar 

  143. 143.

    Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Alizadeh, D. et al. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer. Immunol. Res. 7, 759–772 (2019).

    CAS  Google Scholar 

  145. 145.

    Ma, E. H. et al. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity 51, 856–870.e855 (2019).

    CAS  PubMed  Google Scholar 

  146. 146.

    Zhang, F. et al. Epigenetic manipulation restores functions of defective CD8+ T cells from chronic viral infection. Mol. Ther. 22, 1698–1706 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    McCaw, T. R. et al. Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1. Cancer Immunol. Immunother. 68, 2081–2094 (2019).

    CAS  PubMed  Google Scholar 

  148. 148.

    Zheng, H. et al. HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 22, 4119–4132 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Stephen, T. L. et al. SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity 46, 51–64 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

P.-C.H. was supported in part by a European Research Council Staring Grant (802773-MitoGuide), the Swiss National Science Foundation (31003A_182470), the Swiss Institute for Experimental Cancer Research (ISREC 26075483), the Swiss Cancer League (KFS-3949-08-2016), a Swiss Bridge Award, a Cancer Research Institute–CLIP Investigator award and an EMBO Young Investigator award.

Author information

Affiliations

Authors

Contributions

F.F., A.J., P.R., Y.-R.Y. and P.-C.H. wrote manuscript. A.J. and Y.-R.Y. produced the figures and table.

Corresponding authors

Correspondence to Yi-Ru Yu or Ping-Chih Ho.

Ethics declarations

Competing interests

P.-C.H. is serving as a scientific advisory board member for Elixiron Immunotherapeutics and Acepodia. P.-C.H. receives research grants from Roche and has received honoraria from Pfizer and Chugai. P.R. also receives research grants from Roche. The other authors have no conflict of interest.

Additional information

Peer review information Primary Handling Editor: Pooja Jha.

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

Franco, F., Jaccard, A., Romero, P. et al. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2, 1001–1012 (2020). https://doi.org/10.1038/s42255-020-00280-9

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing