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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).
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.
Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).
Bauer, D. E. et al. Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. FASEB J. 18, 1303–1305 (2004).
Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).
Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).
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).
Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).
Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).
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.
Baitsch, L. et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).
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).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
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.
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).
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).
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).
Sugiura, A. & Rathmell, J. C. Metabolic barriers to T cell function in tumors. J. Immunol. 200, 400–407 (2018).
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).
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.
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.
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).
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).
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).
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).
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).
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).
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).
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
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).
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).
Wang, C., Singer, M. & Anderson, A. C. Molecular dissection of CD8+ T-cell dysfunction. Trends Immunol. 38, 567–576 (2017).
Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017).
Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).
Utzschneider, D. T. et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 14, 603–610 (2013).
Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).
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).
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).
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.
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).
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).
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).
Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).
Nishikawa, H. & Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol. 27, 1–7 (2014).
Wang, H., Franco, F. & Ho, P. C. Metabolic regulation of tregs in cancer: opportunities for immunotherapy. Trends Cancer 3, 583–592 (2017).
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).
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).
Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474–481 (2010).
Ho, P. C. & Liu, P. S. Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. J. Immunother. Cancer 4, 4 (2016).
Li, X. et al. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat. Rev. Clin. Oncol. 16, 425–441 (2019).
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
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).
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).
Speiser, D. E., Ho, P. C. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16, 599–611 (2016).
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).
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).
Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).
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).
Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210 (2019).
Ma, E. H. et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 25, 345–357 (2017).
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).
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).
Barili, V. et al. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nat. Commun. 11, 604 (2020).
MacKenzie, E. D. et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol. Cell. Biol. 27, 3282–3289 (2007).
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).
Palazon, A. et al. An HIF-1alpha/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669–683.e665 (2017).
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).
Najjar, Y. G. et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI Insight 4, e124989 (2019).
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).
Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
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).
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).
Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 16, 880–886 (2010).
Niu, Z. et al. Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat. Commun. 8, 766 (2017).
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).
Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).
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).
Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).
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).
Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).
Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).
Singer, M. et al. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell 166, 1500–1511.e1509 (2016).
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).
Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).
Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019).
Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).
Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).
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).
Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).
Liu, X. et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature 567, 525–529 (2019).
Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).
Franchina, D. G., Dostert, C. & Brenner, D. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol. 39, 489–502 (2018).
Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).
Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).
Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018).
Bengsch, B. et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity 48, 1029–1045.e1025 (2018).
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).
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).
Kemp, K. & Poe, C. Stressed: the unfolded protein response in T cell development, activation, and function. Int. J. Mol. Sci. 20, 1792 (2019).
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).
Song, M. et al. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562, 423–428 (2018).
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).
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).
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).
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).
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).
Teijeira, A. et al. Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation. Cancer Immunol. Res. 6, 798–811 (2018).
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).
Hurst, K. E. et al. Endoplasmic reticulum stress contributes to mitochondrial exhaustion of CD8+ T cells. Cancer Immunol. Res. 7, 476–486 (2019).
Lee, S. & Min, K. T. The interface between ER and mitochondria: molecular compositions and functions. Mol. Cells 41, 1000–1007 (2018).
Namgaladze, D., Khodzhaeva, V. & Brüne, B. ER-mitochondria communication in cells of the innate immune system. Cells 8, 1088 (2019).
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).
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).
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.
MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).
Boland, M. L., Chourasia, A. H. & Macleod, K. F. Mitochondrial dysfunction in cancer. Front. Oncol. 3, 292 (2013).
Quirós, P. M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).
Matilainen, O., Quirós, P. M. & Auwerx, J. Mitochondria and epigenetics: crosstalk in homeostasis and stress. Trends Cell Biol. 27, 453–463 (2017).
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).
Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074.e2065 (2019).
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).
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).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).
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).
Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).
Nabe, S. et al. Reinforce the antitumor activity of CD8+ T cells via glutamine restriction. Cancer Sci. 109, 3737–3750 (2018).
Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).
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).
Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).
Ye, C. & Tu, B. P. Sink into the epigenome: histones as repositories that influence cellular metabolism. Trends Endocrinol. Metab. 29, 626–637 (2018).
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).
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).
Koyama, S. et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 7, 10501 (2016).
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).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
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).
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).
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).
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).
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).
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).
Zhang, F. et al. Epigenetic manipulation restores functions of defective CD8+ T cells from chronic viral infection. Mol. Ther. 22, 1698–1706 (2014).
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).
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).
Stephen, T. L. et al. SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity 46, 51–64 (2017).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
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
Authors and Affiliations
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
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s42255-020-00280-9
This article is cited by
-
Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy
Journal of Hematology & Oncology (2024)
-
Integrative single-cell transcriptomic analyses reveal the cellular ontological and functional heterogeneities of primary and metastatic liver tumors
Journal of Translational Medicine (2024)
-
Fatty acid metabolism of immune cells: a new target of tumour immunotherapy
Cell Death Discovery (2024)
-
Immunological factors linked to geographical variation in vaccine responses
Nature Reviews Immunology (2024)
-
Ex vivo treatment with poly (I:C) alleviates the exhausted phenotype of tumor-infiltrating TCD8+ cells of gastric cancer patients
Naunyn-Schmiedeberg's Archives of Pharmacology (2024)
