Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
08
02
2022
accepted:
19
12
2022
pubmed:
31
1
2023
medline:
3
3
2023
entrez:
30
1
2023
Statut:
ppublish
Résumé
The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.
Identifiants
pubmed: 36717749
doi: 10.1038/s42255-022-00730-6
pii: 10.1038/s42255-022-00730-6
pmc: PMC9970874
doi:
Substances chimiques
Carbon
7440-44-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
314-330Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
Références
Gattinoni, L., Speiser, D. E., Lichterfeld, M. & Bonini, C. T memory stem cells in health and disease. Nat. Med. 23, 18–27 (2017).
pubmed: 28060797
pmcid: 6354775
doi: 10.1038/nm.4241
Gao, S. et al. Stem cell-like memory T cells: a perspective from the dark side. Cell Immunol. 361, 104273 (2021).
pubmed: 33422699
doi: 10.1016/j.cellimm.2020.104273
Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).
pubmed: 25838374
pmcid: 6295668
doi: 10.1126/science.aaa4967
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
pubmed: 29567705
pmcid: 7391259
doi: 10.1126/science.aar4060
Lugli, E., Galletti, G., Boi, S. K. & Youngblood, B. A. Stem, effector, and hybrid states of memory CD8
pubmed: 31810790
doi: 10.1016/j.it.2019.11.004
Galletti, G. et al. Two subsets of stem-like CD8
pubmed: 33046887
pmcid: 7610790
doi: 10.1038/s41590-020-0791-5
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).
pubmed: 21926977
pmcid: 3192229
doi: 10.1038/nm.2446
Franco, F., Jaccard, A., Romero, P., Yu, Y. R. & Ho, P. C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat. Metab. 2, 1001–1012 (2020).
pubmed: 32958939
doi: 10.1038/s42255-020-00280-9
Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8
pubmed: 23080391
pmcid: 4137483
doi: 10.1038/nri3307
Huang, Q. et al. The primordial differentiation of tumor-specific memory CD8
pubmed: 36208623
doi: 10.1016/j.cell.2022.09.020
Siddiqui, I. et al. Intratumoral Tcf1
pubmed: 30635237
doi: 10.1016/j.immuni.2018.12.021
Jeannet, G. et al. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc. Natl Acad. Sci. USA 107, 9777–9782 (2010).
pubmed: 20457902
pmcid: 2906901
doi: 10.1073/pnas.0914127107
Henning, A. N., Roychoudhuri, R. & Restifo, N. P. Epigenetic control of CD8
pubmed: 29379213
pmcid: 6327307
doi: 10.1038/nri.2017.146
Crompton, J. G. et al. Lineage relationship of CD8
pubmed: 25914936
doi: 10.1038/cmi.2015.32
Yu, B. et al. Epigenetic landscapes reveal transcription factors that regulate CD8
pubmed: 28288100
pmcid: 5395420
doi: 10.1038/ni.3706
Araki, Y. et al. Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8
pubmed: 19523850
pmcid: 2709841
doi: 10.1016/j.immuni.2009.05.006
Moller, S. H., Hsueh, P. C., Yu, Y. R., Zhang, L. & Ho, P. C. Metabolic programs tailor T cell immunity in viral infection, cancer, and aging. Cell Metab. 34, 378–395 (2022).
pubmed: 35235773
doi: 10.1016/j.cmet.2022.02.003
Phan, A. T. et al. Constitutive glycolytic metabolism supports CD8
pubmed: 27836431
pmcid: 5130099
doi: 10.1016/j.immuni.2016.10.017
Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210 (2019).
pubmed: 30916644
pmcid: 6497464
doi: 10.7554/eLife.44210
O’Sullivan, D. et al. Memory CD8
pubmed: 25001241
pmcid: 4120664
doi: 10.1016/j.immuni.2014.06.005
Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
pubmed: 19494812
pmcid: 2803086
doi: 10.1038/nature08097
Van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8
pubmed: 22206904
doi: 10.1016/j.immuni.2011.12.007
Boedtkjer, E. & Pedersen, S. F. The acidic tumor microenvironment as a driver of cancer. Annu. Rev. Physiol. 82, 103–126 (2020).
pubmed: 31730395
doi: 10.1146/annurev-physiol-021119-034627
Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).
pubmed: 29634943
pmcid: 7116508
doi: 10.1016/j.ccell.2018.03.012
Scharping, N. E. et al. The tumor microenvironment represses t cell mitochondrial biogenesis to drive intratumoral t cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).
pubmed: 27496732
pmcid: 5207350
doi: 10.1016/j.immuni.2016.07.009
Yu, Y. R. et al. Disturbed mitochondrial dynamics in CD8
pubmed: 33020660
doi: 10.1038/s41590-020-0793-3
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
pubmed: 26321679
pmcid: 4864363
doi: 10.1016/j.cell.2015.08.016
Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).
pubmed: 33398183
pmcid: 7971090
doi: 10.1038/s41590-020-00834-9
Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).
pubmed: 31827286
pmcid: 7108171
doi: 10.1038/s41586-019-1836-5
Im, S. J. et al. Defining CD8
pubmed: 27501248
pmcid: 5297183
doi: 10.1038/nature19330
Haas, R. et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 13, e1002202 (2015).
pubmed: 26181372
pmcid: 4504715
doi: 10.1371/journal.pbio.1002202
Wu, H. et al. T-cells produce acidic niches in lymph nodes to suppress their own effector functions. Nat. Commun. 11, 4113 (2020).
pubmed: 32807791
pmcid: 7431837
doi: 10.1038/s41467-020-17756-7
Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).
pubmed: 22593198
doi: 10.1158/0008-5472.CAN-11-1272
Gottfried, E. et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021 (2006).
pubmed: 16278308
doi: 10.1182/blood-2005-05-1795
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
pubmed: 25043024
pmcid: 4301845
doi: 10.1038/nature13490
Erra Diaz, F. et al. Extracellular acidosis and mTOR inhibition drive the differentiation of human monocyte-derived dendritic cells. Cell Rep. 31, 107613 (2020).
pubmed: 32375041
doi: 10.1016/j.celrep.2020.107613
Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8
pubmed: 24091329
pmcid: 3784544
doi: 10.1172/JCI69589
Scholz, G. et al. Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells. EBioMedicine 4, 50–61 (2016).
pubmed: 26981571
pmcid: 4776068
doi: 10.1016/j.ebiom.2016.01.019
Pollizzi, K. N. et al. mTORC1 and mTORC2 selectively regulate CD8
pubmed: 25893604
pmcid: 4463194
doi: 10.1172/JCI77746
Zhang, L. et al. Mammalian target of rapamycin complex 2 controls CD8 T cell memory differentiation in a Foxo1-dependent manner. Cell Rep. 14, 1206–1217 (2016).
pubmed: 26804903
doi: 10.1016/j.celrep.2015.12.095
Zhou, H. & Huang, S. Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr. Protein Pept. Sci. 12, 30–42 (2011).
pubmed: 21190521
pmcid: 3410744
doi: 10.2174/138920311795659407
Arguello, R. J. et al. SCENITH: a flow cytometry-based method to functionally profile energy metabolism with single-cell resolution. Cell Metab. 32, 1063–1075 (2020).
pubmed: 33264598
pmcid: 8407169
doi: 10.1016/j.cmet.2020.11.007
Ron-Harel, N. et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 24, 104–117 (2016).
pubmed: 27411012
pmcid: 5330619
doi: 10.1016/j.cmet.2016.06.007
Han, C., Ge, M., Ho, P. C. & Zhang, L. Fueling T-cell antitumor immunity: amino acid metabolism revisited. Cancer Immunol. Res. 9, 1373–1382 (2021).
pubmed: 34716193
doi: 10.1158/2326-6066.CIR-21-0459
Kakaradov, B. et al. Early transcriptional and epigenetic regulation of CD8
pubmed: 28218746
pmcid: 5360497
doi: 10.1038/ni.3688
Wang, W. & Zou, W. Amino acids and their transporters in T cell immunity and cancer therapy. Mol. Cell 80, 384–395 (2020).
pubmed: 32997964
pmcid: 7655528
doi: 10.1016/j.molcel.2020.09.006
Marchingo, J. M., Sinclair, L. V., Howden, A. J. & Cantrell, D. A. Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation. eLife 9, e53725 (2020).
Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab. 23, 63–76 (2016).
pubmed: 26674251
doi: 10.1016/j.cmet.2015.11.002
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).
pubmed: 30890531
pmcid: 6687561
doi: 10.1158/2326-6066.CIR-18-0466
Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).
pubmed: 27293185
pmcid: 4974356
doi: 10.1016/j.cell.2016.05.035
Krishna, S. et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 370, 1328–1334 (2020).
pubmed: 33303615
pmcid: 8883579
doi: 10.1126/science.abb9847
Burger, M. L. et al. Antigen dominance hierarchies shape TCF1
pubmed: 34534464
pmcid: 8522630
doi: 10.1016/j.cell.2021.08.020
Guo, Y. et al. Metabolic reprogramming of terminally exhausted CD8
pubmed: 34031618
pmcid: 7610876
doi: 10.1038/s41590-021-00940-2
Klein Geltink, R. I. et al. Metabolic conditioning of CD8
pubmed: 32747793
doi: 10.1038/s42255-020-0256-z
Suzuki, J., Nabe, S., Yasukawa, M. & Yamashita, M. Glutamine regulates the antitumor activity of CD8 T cells. Gan To Kagaku Ryoho 47, 11–15 (2020).
pubmed: 32381854
Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).
pubmed: 30923193
pmcid: 8194369
doi: 10.1126/science.aau0135
Bosticardo, M. et al. Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur. J. Immunol. 31, 2829–2838 (2001).
pubmed: 11536182
doi: 10.1002/1521-4141(200109)31:9<2829::AID-IMMU2829>3.0.CO;2-U
Pucino, V. et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4
pubmed: 31708446
pmcid: 6899510
doi: 10.1016/j.cmet.2019.10.004
Feng, Q. et al. Lactate increases stemness of CD8
pubmed: 36068198
pmcid: 9448806
doi: 10.1038/s41467-022-32521-8
Roy, D. G. et al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab. 31, 250–266 (2020).
pubmed: 32023446
doi: 10.1016/j.cmet.2020.01.006
Zhang, L. & Romero, P. Metabolic control of CD8
pubmed: 29246759
doi: 10.1016/j.molmed.2017.11.005
Cham, C. M., Driessens, G., O’Keefe, J. P. & Gajewski, T. F. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8
pubmed: 18792400
pmcid: 3008428
doi: 10.1002/eji.200838289
O’Sullivan, D. et al. Memory CD8
pubmed: 30134202
pmcid: 6167519
doi: 10.1016/j.immuni.2018.07.018
Lin, R. et al. Fatty acid oxidation controls CD8
pubmed: 32075801
doi: 10.1158/2326-6066.CIR-19-0702
Raud, B. et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. 28, 504–515 (2018).
pubmed: 30043753
pmcid: 6747686
doi: 10.1016/j.cmet.2018.06.002
Sharma, U. & Rando, O. J. Metabolic inputs into the epigenome. Cell Metab. 25, 544–558 (2017).
pubmed: 28273477
doi: 10.1016/j.cmet.2017.02.003
Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8
pubmed: 27798602
pmcid: 5149074
doi: 10.1038/nature20165
Zhang, H. et al. Ketogenesis-generated beta-hydroxybutyrate is an epigenetic regulator of CD8
pubmed: 31871320
doi: 10.1038/s41556-019-0440-0
Bian, Y. et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585, 277–282 (2020).
pubmed: 32879489
pmcid: 7486248
doi: 10.1038/s41586-020-2682-1
Wall, M. et al. Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. Blood 112, 2305–2317 (2008).
pubmed: 18621930
doi: 10.1182/blood-2007-09-111856
Yerinde, C., Siegmund, B., Glauben, R. & Weidinger, C. Metabolic control of epigenetics and its role in CD8
pubmed: 31849941
pmcid: 6901948
doi: 10.3389/fimmu.2019.02718
Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).
pubmed: 27626381
pmcid: 5204372
doi: 10.1038/nature19364
Guo, A. et al. cBAF complex components and MYC cooperate early in CD8
pubmed: 35732731
pmcid: 9623036
doi: 10.1038/s41586-022-04849-0
Raynor, J. L., Chapman, N. M. & Chi, H. Metabolic control of memory T-cell generation and stemness. Cold Spring Harb. Perspect. Biol. 13, a037770 (2021).
pubmed: 33820774
doi: 10.1101/cshperspect.a037770
Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).
pubmed: 31036827
pmcid: 6488672
doi: 10.1038/s41467-019-09982-5
Jin, H. et al. ChIPseqSpikeInFree: a ChIP–seq normalization approach to reveal global changes in histone modifications without spike-in. Bioinformatics 36, 1270–1272 (2020).
pubmed: 31566663
doi: 10.1093/bioinformatics/btz720
Sellick, C. A., Hansen, R., Stephens, G. M., Goodacre, R. & Dickson, A. J. Metabolite extraction from suspension-cultured mammalian cells for global metabolite profiling. Nat. Protoc. 6, 1241–1249 (2011).
pubmed: 21799492
doi: 10.1038/nprot.2011.366
Li, C. et al. Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2–eIF2α axis. Cell Stem Cell 29, 1119–1134 (2022).
pubmed: 35803229
doi: 10.1016/j.stem.2022.06.004
Wenes, M. et al. The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function. Cell Metab. 34, 731–746 (2022).
pubmed: 35452600
pmcid: 9116152
doi: 10.1016/j.cmet.2022.03.013