The therapeutic implications of immunosuppressive tumor aerobic glycolysis.
cancer
glycolysis
immunology
metabolism
Journal
Cellular & molecular immunology
ISSN: 2042-0226
Titre abrégé: Cell Mol Immunol
Pays: China
ID NLM: 101242872
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
11
05
2021
accepted:
27
05
2021
pubmed:
10
7
2021
medline:
1
4
2022
entrez:
9
7
2021
Statut:
ppublish
Résumé
In 2011, Hanahan and Weinberg added "Deregulating Cellular Energetics" and "Avoiding Immune Destruction" to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.
Identifiants
pubmed: 34239083
doi: 10.1038/s41423-021-00727-3
pii: 10.1038/s41423-021-00727-3
pmc: PMC8752729
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
46-58Subventions
Organisme : NCI NIH HHS
ID : F30 CA247202
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA217987
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007347
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to CSI and USTC.
Références
Warburg O, Negelein E, Posener K. Versuche an Überlebendem Carcinomgewebe. Klinische Wochenschr. 1924;3:1062–1064.
doi: 10.1007/BF01736087
Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.
pubmed: 13298683
doi: 10.1126/science.123.3191.309
Andrejeva G, Rathmell JC. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 2017;26:49–70.
pubmed: 28683294
pmcid: 5555084
doi: 10.1016/j.cmet.2017.06.004
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.
doi: 10.1126/science.1160809
O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.
pubmed: 27396447
pmcid: 5001910
doi: 10.1038/nri.2016.70
Ward PS, Thompson CB. Signaling in control of cell growth and metabolism. Cold Spring Harb Perspect Biol. 2012;4:a006783.
pubmed: 22687276
pmcid: 3385956
doi: 10.1101/cshperspect.a006783
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76.
pubmed: 28283069
pmcid: 5394987
doi: 10.1016/j.cell.2017.02.004
Orozco JM, Krawczyk PA, Scaria SM, Cangelosi AL, Chan SH, Kunchok T, et al. Dihydroxyacetone phosphate signals glucose availability to mTORC1. Nat Metab. 2020;2:893–901.
pubmed: 32719541
pmcid: 7995735
doi: 10.1038/s42255-020-0250-5
Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev. 2012;249:43–58.
pubmed: 22889214
pmcid: 3419491
doi: 10.1111/j.1600-065X.2012.01152.x
Wolfson RL, Sabatini DM. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 2017;26:301–309.
pubmed: 28768171
pmcid: 5560103
doi: 10.1016/j.cmet.2017.07.001
Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, et al. c-Myc regulates transcriptional pause release. Cell. 2010;141:432–45.
pubmed: 20434984
pmcid: 2864022
doi: 10.1016/j.cell.2010.03.030
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000;275:21797–800.
pubmed: 10823814
doi: 10.1074/jbc.C000023200
Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O'Donnell KA, et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol. 2004;24:5923–36.
pubmed: 15199147
pmcid: 480875
doi: 10.1128/MCB.24.13.5923-5936.2004
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7.
pubmed: 19033189
pmcid: 2596212
doi: 10.1073/pnas.0810199105
Kim J, Lee JH, Iyer VR. Global identification of Myc target genes reveals its direct role in mitochondrial biogenesis and its E-box usage in vivo. PLoS ONE. 2008;3:e1798.
pubmed: 18335064
pmcid: 2258436
doi: 10.1371/journal.pone.0001798
Meric-Bernstam F, Brusco L, Shaw K, Horombe C, Kopetz S, Davies MA, et al. Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials. J Clin Oncol. 2015;33:2753–62.
pubmed: 26014291
pmcid: 4550690
doi: 10.1200/JCO.2014.60.4165
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.
pubmed: 26771115
pmcid: 4715268
doi: 10.1016/j.cmet.2015.12.006
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
pubmed: 21376230
doi: 10.1016/j.cell.2011.02.013
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.
pubmed: 23890059
doi: 10.1016/j.immuni.2013.07.012
Galluzzi, L, Chan TA, Kroemer G, Wolchok JD, López-Soto A, The hallmarks of successful anticancer immunotherapy. Sci Transl Med. 2018;10.
Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014;20:61–72.
pubmed: 24930970
pmcid: 4079750
doi: 10.1016/j.cmet.2014.05.004
Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35:871–82.
pubmed: 22195744
pmcid: 3248798
doi: 10.1016/j.immuni.2011.09.021
Palazon A, Tyrakis PA, Macias D, Veliça P, Rundqvist H, Fitzpatrick S, et al. An HIF-1alpha/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell. 2017;32:669–683 e5.
pubmed: 29136509
pmcid: 5691891
doi: 10.1016/j.ccell.2017.10.003
Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat. Immunol. 2013;14:1173–82.
pubmed: 24076634
pmcid: 3977965
doi: 10.1038/ni.2714
Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, et al. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell. 2016;166:1117–1131 e14.
pubmed: 27565342
pmcid: 5548538
doi: 10.1016/j.cell.2016.07.032
Kaymak I, Williams KS, Cantor JR, Jones RG. Immunometabolic interplay in the tumor microenvironment. Cancer Cell. 2021;39:28–37.
pubmed: 33125860
doi: 10.1016/j.ccell.2020.09.004
Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A, Contreras DC, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell. 2018;175:1780–1795 e19.
pubmed: 30392958
pmcid: 6361668
doi: 10.1016/j.cell.2018.10.001
Basu S, Hubbard B, Shevach EM. Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells. J. Leukoc. Biol. 2015;97:279–83.
pubmed: 25492937
doi: 10.1189/jlb.2AB0514-273RR
Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM, Martínez-Reyes I, et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature. 2019;565:495–499.
pubmed: 30626970
pmcid: 6345596
doi: 10.1038/s41586-018-0846-z
Watson MJ, Vignali P, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021;591:645–51.
pubmed: 33589820
pmcid: 7990682
doi: 10.1038/s41586-020-03045-2
Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–77.
pubmed: 12121659
doi: 10.1016/S1074-7613(02)00323-0
Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature. 2021;591:652–658.
pubmed: 33588426
pmcid: 8057670
doi: 10.1038/s41586-021-03326-4
Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol. 2016;17:1459–66.
pubmed: 27695003
pmcid: 5215903
doi: 10.1038/ni.3577
Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol. 2015;16:188–96.
pubmed: 25559257
pmcid: 4297515
doi: 10.1038/ni.3077
Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol. 2015;16:178–87.
pubmed: 25559258
pmcid: 4297581
doi: 10.1038/ni.3076
Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.
pubmed: 25809635
doi: 10.1038/ncomms7692
Boussiotis VA, Chatterjee P, Li L. Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J. 2014;20:265–71.
pubmed: 25098287
pmcid: 4151049
doi: 10.1097/PPO.0000000000000059
Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67.
pubmed: 28990585
doi: 10.1038/nri.2017.108
Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, 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. 2014;41:802–14.
pubmed: 25464856
pmcid: 4270830
doi: 10.1016/j.immuni.2014.10.013
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53.
pubmed: 16227604
pmcid: 1265804
doi: 10.1128/MCB.25.21.9543-9553.2005
Previte DM, Martins CP, O'Connor EC, Marre ML, Coudriet GM, Beck NW, et al. Lymphocyte activation Gene-3 maintains mitochondrial and metabolic quiescence in naive CD4(+) T Cells. Cell Rep. 2019;27:129–141 e4.
pubmed: 30943396
doi: 10.1016/j.celrep.2019.03.004
He W, Zhang H, Han F, Chen X, Lin R, Wang W, et al. CD155T/TIGIT signaling regulates CD8(+) T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res. 2017;77:6375–88.
pubmed: 28883004
doi: 10.1158/0008-5472.CAN-17-0381
Lee MJ, Yun SJ, Lee B, Jeong E, Yoon G, Kim K, et al. Association of TIM-3 expression with glucose metabolism in Jurkat T cells. BMC Immunol. 2020;21:48.
pubmed: 32819283
pmcid: 7441550
doi: 10.1186/s12865-020-00377-6
Sabharwal SS, Rosen DB, Grein J, Tedesco D, Joyce-Shaikh B, Ueda R, et al. GITR agonism enhances cellular metabolism to support CD8(+) T-cell proliferation and effector cytokine production in a mouse tumor model. Cancer Immunol Res. 2018;6:1199–211.
pubmed: 30154083
doi: 10.1158/2326-6066.CIR-17-0632
Choi BK, Lee DY, Lee DG, Kim YH, Kim SH, Oh HS, et al. 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8(+) T cell proliferation. Cell Mol Immunol. 2017;14:748–57.
pubmed: 26972770
doi: 10.1038/cmi.2016.02
Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 2018;215:1091–100.
pubmed: 29511066
pmcid: 5881463
doi: 10.1084/jem.20171068
Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581–90.
pubmed: 25939063
pmcid: 4458184
doi: 10.1038/nm.3838
Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T Cells. Immunity. 2016;44:380–90.
pubmed: 26885860
doi: 10.1016/j.immuni.2016.01.021
Zeng H, Cohen S, Guy C, Shrestha S, Neale G, Brown SA, et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity. 2016;45:540–54.
pubmed: 27637146
pmcid: 5050556
doi: 10.1016/j.immuni.2016.08.017
Palmer CS, Duette GA, Wagner M, Henstridge DC, Saleh S, Pereira C, et al. Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection. FEBS Lett. 2017;591:3319–32.
pubmed: 28892135
pmcid: 5658250
doi: 10.1002/1873-3468.12843
Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E, Faicchia D, et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci USA. 2018;115:E6546–E6555.
pubmed: 29941600
pmcid: 6048537
doi: 10.1073/pnas.1720113115
Buchan SL, Fallatah M, Thirdborough SM, Taraban VY, Rogel A, Thomas LJ, et al. PD-1 Blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8(+) T-cell-driven antitumor immunity. Clin Cancer Res. 2018;24:2383–94.
pubmed: 29514845
pmcid: 5959006
doi: 10.1158/1078-0432.CCR-17-3057
Beharry Z, Mahajan S, Zemskova M, Lin YW, Tholanikunnel BG, Xia Z, et al. The Pim protein kinases regulate energy metabolism and cell growth. Proc Natl Acad Sci USA. 2011;108:528–33.
pubmed: 21187426
doi: 10.1073/pnas.1013214108
Peperzak V, Veraar EA, Keller AM, Xiao Y, Borst J. The Pim kinase pathway contributes to survival signaling in primed CD8+ T cells upon CD27 costimulation. J Immunol. 2010;185:6670–8.
pubmed: 21048108
doi: 10.4049/jimmunol.1000159
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.
pubmed: 12091876
doi: 10.1038/nm730
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.
pubmed: 11015443
pmcid: 2193311
doi: 10.1084/jem.192.7.1027
Jalali S, Price-Troska T, Bothun C, Villasboas J, Kim HJ, Yang ZZ, et al. Reverse signaling via PD-L1 supports malignant cell growth and survival in classical Hodgkin lymphoma. Blood Cancer J. 2019;9:22.
pubmed: 30783096
pmcid: 6381098
doi: 10.1038/s41408-019-0185-9
Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111:3635–43.
pubmed: 18223165
pmcid: 2275025
doi: 10.1182/blood-2007-11-123141
Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–41.
pubmed: 26321679
pmcid: 4864363
doi: 10.1016/j.cell.2015.08.016
Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665–74.
pubmed: 24336068
doi: 10.1158/0008-5472.CAN-13-0992
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812–9.
pubmed: 17255361
doi: 10.1182/blood-2006-07-035972
Huang A, Peng D, Guo H, Ben Y, Zuo X, Wu F, et al. A human programmed death-ligand 1-expressing mouse tumor model for evaluating the therapeutic efficacy of anti-human PD-L1 antibodies. Sci. Rep. 2017;7:42687.
pubmed: 28202921
pmcid: 5311961
doi: 10.1038/srep42687
Wang L, Kang FB, Shan BE. B7-H3-mediated tumor immunology: friend or foe? Int J. Cancer. 2014;134:2764–71.
pubmed: 24013874
doi: 10.1002/ijc.28474
Liu H, Tekle C, Chen YW, Kristian A, Zhao Y, Zhou M, et al. B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol Cancer Ther. 2011;10:960–71.
pubmed: 21518725
pmcid: 3253760
doi: 10.1158/1535-7163.MCT-11-0072
Tekle C, Nygren MK, Chen YW, Dybsjord I, Nesland JM, Maelandsmo GM, et al. B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. Int J Cancer. 2012;130:2282–90.
pubmed: 21671471
doi: 10.1002/ijc.26238
Zhao X, Li DC, Zhu XG, Gan WJ, Li Z, Xiong F, et al. B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int J Mol Med. 2013;31:283–91.
pubmed: 23242015
doi: 10.3892/ijmm.2012.1212
Zhao X, Zhang GB, Gan WJ, Xiong F, Li Z, Zhao H, et al. Silencing of B7-H3 increases gemcitabine sensitivity by promoting apoptosis in pancreatic carcinoma. Oncol Lett. 2013;5:805–12.
pubmed: 23426281
pmcid: 3576185
doi: 10.3892/ol.2013.1118
Chen YW, Tekle C, Fodstad O. The immunoregulatory protein human B7H3 is a tumor-associated antigen that regulates tumor cell migration and invasion. Curr Cancer Drug Targets. 2008;8:404–13.
pubmed: 18690846
doi: 10.2174/156800908785133141
Lim S, Liu H, Madeira da Silva L, Arora R, Liu Z, Phillips JB, et al. Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1alpha. Cancer Res. 2016;76:2231–42.
pubmed: 27197253
pmcid: 4874665
doi: 10.1158/0008-5472.CAN-15-1538
Nunes-Xavier CE, Karlsen KF, Tekle C, Pedersen C, Øyjord T, Hongisto V, et al. Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors. Oncotarget. 2016;7:6891–901.
pubmed: 26771843
pmcid: 4872756
doi: 10.18632/oncotarget.6902
Shi T, Ma Y, Cao L, Zhan S, Xu Y, Fu F, et al. B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2. Cell Death Dis. 2019;10:308.
pubmed: 30952834
pmcid: 6450969
doi: 10.1038/s41419-019-1549-6
Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity. 2003;18:849–61.
pubmed: 12818165
doi: 10.1016/S1074-7613(03)00152-3
Saha, A, et al., Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality. JCI Insight. 2019;4.
Siska, PJ, et al., Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. 2017;2.
Beckermann, KE, et al., CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation. JCI Insight. 2020;5.
Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, et al. Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell. 2017;32:377–391 e9.
pubmed: 28898698
pmcid: 5751418
doi: 10.1016/j.ccell.2017.08.004
Miranda-Gonçalves V, Granja S, Martinho O, Honavar M, Pojo M, Costa BM, et al. Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas. Oncotarget. 2016;7:46335–53.
pubmed: 27331625
pmcid: 5216802
doi: 10.18632/oncotarget.10114
Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J. Biol. Chem. 2006;281:9030–7.
pubmed: 16452478
doi: 10.1074/jbc.M511397200
Firth JD, Ebert BL, Ratcliffe PJ. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem. 1995;270:21021–7.
pubmed: 7673128
doi: 10.1074/jbc.270.36.21021
Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol. 2006;291:L941–9.
pubmed: 16766575
doi: 10.1152/ajplung.00528.2005
Mookerjee SA, Goncalves R, Gerencser AA, Nicholls DG, Brand MD. The contributions of respiration and glycolysis to extracellular acid production. Biochim Biophys Acta. 2015;1847:171–81.
pubmed: 25449966
doi: 10.1016/j.bbabio.2014.10.005
Svastová E, Hulíková A, Rafajová M, Zat'ovicová M, Gibadulinová A, Casini A, et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 2004;577:439–45.
pubmed: 15556624
doi: 10.1016/j.febslet.2004.10.043
Sullivan, MR, et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife, 2019;8.
Rademakers SE, Lok J, van der Kogel AJ, Bussink J, Kaanders JH. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer. 2011;11:167.
pubmed: 21569415
pmcid: 3115911
doi: 10.1186/1471-2407-11-167
Scharping NE, Rivadeneira DB, Menk AV, Vignali P, Ford BR, Rittenhouse NL, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021;22:205–15.
pubmed: 33398183
pmcid: 7971090
doi: 10.1038/s41590-020-00834-9
Chafe SC, Lou Y, Sceneay J, Vallejo M, Hamilton MJ, McDonald PC, et al. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production. Cancer Res. 2015;75:996–1008.
pubmed: 25623234
doi: 10.1158/0008-5472.CAN-14-3000
Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 2019;29:135–50 e9.
pubmed: 31577944
doi: 10.1016/j.celrep.2019.08.068
Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27:977–987 e4.
pubmed: 29628419
pmcid: 5932208
doi: 10.1016/j.cmet.2018.02.024
Jaiswal AR, Liu AJ, Pudakalakatti S, Dutta P, Jayaprakash P, Bartkowiak T, et al. Melanoma evolves complete immunotherapy resistance through the acquisition of a hypermetabolic phenotype. Cancer Immunol Res. 2020;8:1365–1380.
pubmed: 32917656
pmcid: 7642111
doi: 10.1158/2326-6066.CIR-19-0005
Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer. 2012;131:633–40.
pubmed: 21898391
doi: 10.1002/ijc.26410
Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24:657–671.
pubmed: 27641098
doi: 10.1016/j.cmet.2016.08.011
Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25:1282–1293 e7.
pubmed: 28416194
pmcid: 5462872
doi: 10.1016/j.cmet.2016.12.018
Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.
pubmed: 22419253
doi: 10.1038/nrc3245
Cortese N, Capretti G, Barbagallo M, Rigamonti A, Takis PG, Castino GF, et al. Metabolome of pancreatic juice delineates distinct clinical profiles of pancreatic cancer and reveals a link between glucose metabolism and PD-1(+) cells. Cancer Immunol. Res. 2020;8:493–505.
pubmed: 32019781
doi: 10.1158/2326-6066.CIR-19-0403
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–63.
pubmed: 25043024
pmcid: 4301845
doi: 10.1038/nature13490
Errea A, Cayet D, Marchetti P, Tang C, Kluza J, Offermanns S, et al. Lactate inhibits the pro-inflammatory response and metabolic reprogramming in murine macrophages in a GPR81-independent manner. PLoS ONE. 2016;11:e0163694.
pubmed: 27846210
pmcid: 5112849
doi: 10.1371/journal.pone.0163694
Gottfried E, Kunz-Schughart LA, Ebner S, MuellerKlieser W, Hoves S, Andreesen R, et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006;107:2013–21\
pubmed: 16278308
doi: 10.1182/blood-2005-05-1795
Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol. 2010;184:1200–9.
pubmed: 20026743
doi: 10.4049/jimmunol.0902584
Wu H, Estrella V, Beatty M, Abrahams D, El-Kenawi A, Russell S, et al. T-cells produce acidic niches in lymph nodes to suppress their own effector functions. Nat Commun. 2020;11:4113.
pubmed: 32807791
pmcid: 7431837
doi: 10.1038/s41467-020-17756-7
Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72:2746–56.
pubmed: 22593198
doi: 10.1158/0008-5472.CAN-11-1272
Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 2016;76:1381–90.
pubmed: 26719539
doi: 10.1158/0008-5472.CAN-15-1743
Chafe SC, McDonald PC, Saberi S, Nemirovsky O, Venkateswaran G, Burugu S, et al. Targeting hypoxia-induced carbonic anhydrase IX enhances immune-checkpoint blockade locally and systemically. Cancer Immunol Res. 2019;7:1064–1078.
pubmed: 31088846
doi: 10.1158/2326-6066.CIR-18-0657
Pötzl J, Roser D, Bankel L, Hömberg N, Geishauser A, Brenner CD, et al. Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-gamma and induces NK cell-dependent lymphoma control without other immunotherapies. Int J Cancer. 2017;140:2125–2133.
pubmed: 28195314
doi: 10.1002/ijc.30646
Sinclair LV, Barthelemy C, Cantrell DA. Single cell glucose uptake assays: a cautionary tale. Immunometabolism. 2020;2:e200029.
pubmed: 32879737
pmcid: 7116014
doi: 10.20900/immunometab20200029
Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015;162:1217–28.
pubmed: 26321681
pmcid: 4567953
doi: 10.1016/j.cell.2015.08.012
Reinfeld, BI, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature.2021.
Sinclair, LV, et al. Antigen receptor control of methionine metabolism in T cells. Elife. 2019;8.
Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S, Crespo J, et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature. 2020;585:277–282.
pubmed: 32879489
pmcid: 7486248
doi: 10.1038/s41586-020-2682-1
Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ. Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res. 1996;56:3436–40.
pubmed: 8758908
Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92:4150–66.
pubmed: 9834220
doi: 10.1182/blood.V92.11.4150
Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Ioannou K, Ziogas AC, et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br J Cancer. 2012;107:1869–75.
pubmed: 23169339
pmcid: 3504940
doi: 10.1038/bjc.2012.468
Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212:139–48.
pubmed: 25601652
pmcid: 4322048
doi: 10.1084/jem.20140559
Klose R, Krzywinska E, Castells M, Gotthardt D, Putz EM, Kantari-Mimoun C, et al. Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia. Nat Commun. 2016;7:12528.
pubmed: 27538380
pmcid: 4992172
doi: 10.1038/ncomms12528
Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15:2148–57.
pubmed: 19276286
doi: 10.1158/1078-0432.CCR-08-1332
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–1127.
pubmed: 30779529
doi: 10.1056/NEJMoa1816714
Huang T, Cheng X, Chahoud J, Sarhan A, Tamboli P, Rao P, et al. Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nat Commun. 2020;11:2124.
pubmed: 32358507
pmcid: 7195486
doi: 10.1038/s41467-020-15980-9
McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749–757.
pubmed: 29867230
pmcid: 6721896
doi: 10.1038/s41591-018-0053-3
Chiu DK, Tse AP, Xu IM, Di Cui J, Lai RK, Li LL, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun. 2017;8:517.
pubmed: 28894087
pmcid: 5593860
doi: 10.1038/s41467-017-00530-7
Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, et al. Ecto-5’-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest. 2002;110:993–1002.
pubmed: 12370277
pmcid: 151145
doi: 10.1172/JCI0215337
Borges da Silva H, Beura LK, Wang H, Hanse EA, Gore R, Scott MC, et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8(+) T cells. Nature. 2018;559:264–268.
pubmed: 29973721
doi: 10.1038/s41586-018-0282-0
Granstein RD, Ding W, Huang J, Holzer A, Gallo RL, Di Nardo A, et al. Augmentation of cutaneous immune responses by ATP gamma S: purinergic agonists define a novel class of immunologic adjuvants. J Immunol. 2005;174:7725–31.
pubmed: 15944274
doi: 10.4049/jimmunol.174.12.7725
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA. 2006;103:13132–7.
pubmed: 16916931
pmcid: 1559765
doi: 10.1073/pnas.0605251103
Ohta A, Ohta A, Madasu M, Kini R, Subramanian M, Goel N, et al. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol. 2009;183:5487–93.
pubmed: 19843934
doi: 10.4049/jimmunol.0901247
Sevigny CP, Li L, Awad AS, Huang L, McDuffie M, Linden J, et al. Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. J Immunol. 2007;178:4240–9.
pubmed: 17371980
doi: 10.4049/jimmunol.178.7.4240
Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS, Messaoudene M, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 2018;78:1003–1016.
pubmed: 29229601
doi: 10.1158/0008-5472.CAN-17-2826
Lokshin A, Raskovalova T, Huang X, Zacharia LC, Jackson EK, Gorelik E. Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res. 2006;66:7758–65.
pubmed: 16885379
doi: 10.1158/0008-5472.CAN-06-0478
Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri TK, et al. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell. Cancer Cancer Disco. 2020;10:40–53.
doi: 10.1158/2159-8290.CD-19-0980
Linehan WM, Schmidt LS, Crooks DR, Wei D, Srinivasan R, Lang M, et al. The metabolic basis of kidney. Cancer Cancer Disco. 2019;9:1006–1021.
doi: 10.1158/2159-8290.CD-18-1354
Sorrentino C, Miele L, Porta A, Pinto A, Morello S. Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget. 2015;6:27478–89.
pubmed: 26317647
pmcid: 4695003
doi: 10.18632/oncotarget.4393
Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia. 2013;15:1400–9.
pubmed: 24403862
pmcid: 3884531
doi: 10.1593/neo.131748
Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013;19:5626–35.
pubmed: 23983257
doi: 10.1158/1078-0432.CCR-13-0545
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–1290.
pubmed: 29562145
pmcid: 5972549
doi: 10.1056/NEJMoa1712126
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.
pubmed: 26027431
pmcid: 5698905
doi: 10.1056/NEJMoa1504030
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078–2092.
pubmed: 29658856
doi: 10.1056/NEJMoa1801005
Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.
pubmed: 25838373
doi: 10.1126/science.aaa8172
Xin Yu J, Hodge JP, Oliva C, Neftelinov ST, Hubbard-Lucey VM, Tang J. Trends in clinical development for PD-1/PD-L1 inhibitors. Nat Rev Drug Disco. 2020;19:163–164.
doi: 10.1038/d41573-019-00182-w
Pan M, Reid MA, Lowman XH, Kulkarni RP, Tran TQ, Liu X, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016;18:1090–101.
pubmed: 27617932
pmcid: 5536113
doi: 10.1038/ncb3410
Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16:619–34.
pubmed: 27492215
pmcid: 5484415
doi: 10.1038/nrc.2016.71
Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019;366:1013–1021.
pubmed: 31699883
pmcid: 7023461
doi: 10.1126/science.aav2588
Meric-Bernstam F, Lee RJ, Carthon BC, Iliopoulos O, Mier JW, Patel MR, et al. CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): results of a phase I study. J Clin Oncol. 2019;37:549–549.
doi: 10.1200/JCO.2019.37.7_suppl.549
Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018;24:194–202.
pubmed: 29334372
pmcid: 5803339
doi: 10.1038/nm.4464
Byun JK, Park M, Lee S, Yun JW, Lee J, Kim JS, et al. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol Cell. 2020;80:592–606 e8.
pubmed: 33159855
doi: 10.1016/j.molcel.2020.10.015
Edwards, DN, et al., Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest. 2021;131.
Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017;18:985–994.
pubmed: 28714978
doi: 10.1038/ni.3796
Palmieri EM, Menga A, Martín-Pérez R, Quinto A, Riera-Domingo C, De Tullio G, et al. Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Cell Rep. 2017;20:1654–1666.
pubmed: 28813676
pmcid: 5575233
doi: 10.1016/j.celrep.2017.07.054
Oh MH, Sun IH, Zhao L, Leone RD, Sun IM, Xu W, et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest. 2020;130:3865–3884.
pubmed: 32324593
pmcid: 7324212
doi: 10.1172/JCI131859
Kono M, Yoshida N, Maeda K, Suárez-Fueyo A, Kyttaris VC, Tsokos GC. Glutaminase 1 inhibition reduces glycolysis and ameliorates lupus-like disease in MRL/lpr mice and experimental autoimmune Encephalomyelitis. Arthritis Rheumatol. 2019;71:1869–1878.
pubmed: 31233276
pmcid: 6817384
doi: 10.1002/art.41019
Wang J, Ye C, Chen C, Xiong H, Xie B, Zhou J, et al. Glucose transporter GLUT1 expression and clinical outcome in solid tumors: a systematic review and meta-analysis. Oncotarget. 2017;8:16875–16886.
pubmed: 28187435
pmcid: 5370007
doi: 10.18632/oncotarget.15171
Yu M, Yongzhi H, Chen S, Luo X, Lin Y, Zhou Y, et al. The prognostic value of GLUT1 in cancers: a systematic review and meta-analysis. Oncotarget. 2017;8:43356–43367.
pubmed: 28498810
pmcid: 5522151
doi: 10.18632/oncotarget.17445
Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med. 2011;3:94ra70.
pubmed: 21813754
pmcid: 3683134
doi: 10.1126/scitranslmed.3002394
Contat C, Ancey PB, Zangger N, Sabatino S, Pascual J, Escrig S, et al. Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth. Elife. 2020;9:9.
doi: 10.7554/eLife.53618
Freemerman AJ, Zhao L, Pingili AK, Teng B, Cozzo AJ, Fuller AM, et al. Myeloid Slc2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1. J Immunol. 2019;202:1265–1286.
pubmed: 30659108
pmcid: 6360258
doi: 10.4049/jimmunol.1800002
Du X, Wen J, Wang Y, Karmaus P, Khatamian A, Tan H, et al. Hippo/Mst signalling couples metabolic state and immune function of CD8alpha(+) dendritic cells. Nature. 2018;558:141–145.
pubmed: 29849151
pmcid: 6292204
doi: 10.1038/s41586-018-0177-0
Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest. 2013;123:4479–88.
pubmed: 24091329
pmcid: 3784544
doi: 10.1172/JCI69589
Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil RL, et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 2015;75:296–305.
pubmed: 25432172
doi: 10.1158/0008-5472.CAN-14-2277
Evans CA, Liu T, Lescarbeau A, Nair SJ, Grenier L, Pradeilles JA, et al. Discovery of a selective phosphoinositide-3-kinase (PI3K)-gamma Inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med Chem. Lett. 2016;7:862–7.
pubmed: 27660692
pmcid: 5018865
doi: 10.1021/acsmedchemlett.6b00238
Kaneda MM, Cappello P, Nguyen AV, Ralainirina N, Hardamon CR, Foubert P, et al. Macrophage PI3Kgamma drives pancreatic ductal adenocarcinoma progression. Cancer Disco. 2016;6:870–85.
doi: 10.1158/2159-8290.CD-15-1346
Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19:715–27.
pubmed: 21665146
pmcid: 3144144
doi: 10.1016/j.ccr.2011.04.016
Foubert P, Kaneda MM, Varner JA. PI3Kgamma activates integrin alpha4 and promotes immune suppressive myeloid cell polarization during tumor progression. Cancer Immunol Res. 2017;5:957–968.
pubmed: 28963139
pmcid: 6422969
doi: 10.1158/2326-6066.CIR-17-0143
Torres C, Mancinelli G, Cordoba-Chacon J, Viswakarma N, Castellanos K, Grimaldo S, et al. p110gamma deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity. Proc Natl Acad Sci USA. 2019;116:14724–14733.
pubmed: 31266893
pmcid: 6642408
doi: 10.1073/pnas.1813012116
González-García A, Sánchez-Ruiz J, Flores JM, Carrera AC. Phosphatidylinositol 3-kinase gamma inhibition ameliorates inflammation and tumor growth in a model of colitis-associated cancer. Gastroenterology. 2010;138:1374–83.
pubmed: 20004201
doi: 10.1053/j.gastro.2009.12.001
De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature. 2016;539:443–447.
pubmed: 27828943
pmcid: 5634331
doi: 10.1038/nature20554
Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature. 2016;539:437–442.
pubmed: 27642729
pmcid: 5479689
doi: 10.1038/nature19834
Zhang X, Shen L, Liu Q, Hou L, Huang L. Inhibiting PI3 kinase-gamma in both myeloid and plasma cells remodels the suppressive tumor microenvironment in desmoplastic tumors. J. Control Release. 2019;309:173–180.
pubmed: 31362079
pmcid: 6815713
doi: 10.1016/j.jconrel.2019.07.039
Joshi S, Singh AR, Liu KX, Pham TV, Zulcic M, Skola D, et al. SF2523: Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer. Mol Cancer Ther. 2019;18:1036–1044.
pubmed: 31018997
pmcid: 6893301
doi: 10.1158/1535-7163.MCT-18-1206
Qin H, Yu H, Sheng J, Zhang D, Shen N, Liu L, et al. PI3Kgamma inhibitor attenuates immunosuppressive effect of Poly(l-Glutamic Acid)-combretastatin A4 conjugate in metastatic breast cancer. Adv Sci (Weinh.) 2019;6:1900327.
pubmed: 31380170
Gyori, D, et al., Class (I) Phosphoinositide 3-Kinases in the Tumor Microenvironment. Cancers (Basel). 2017;9.
Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, et al. Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science. 2000;287:1040–6.
pubmed: 10669416
doi: 10.1126/science.287.5455.1040
Chow MT, Ozga AJ, Servis RL, Frederick DT, Lo JA, Fisher DE, et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity. 2019;50:1498–1512 e5.
pubmed: 31097342
pmcid: 6527362
doi: 10.1016/j.immuni.2019.04.010
Barbi J, Cummings HE, Lu B, Oghumu S, Rückle T, Rommel C, et al. PI3Kgamma (PI3Kgamma) is essential for efficient induction of CXCR3 on activated T cells. Blood. 2008;112:3048–51.
pubmed: 18658026
pmcid: 2569163
doi: 10.1182/blood-2008-02-135715
Uehara M, McGrath MM, Ohori S, Solhjou Z, Banouni N, Routray S, et al. Regulation of T cell alloimmunity by PI3Kgamma and PI3Kdelta. Nat Commun. 2017;8:951.
pubmed: 29038423
pmcid: 5643371
doi: 10.1038/s41467-017-00982-x
Dwyer CJ, Arhontoulis DC, Rangel Rivera GO, Knochelmann HM, Smith AS, Wyatt MM, et al. Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8(+) T cells. Eur J Immunol. 2020;50:1386–1399.
pubmed: 32383488
pmcid: 7496332
doi: 10.1002/eji.201948455
Tassi I, Cella M, Gilfillan S, Turnbull I, Diacovo TG, Penninger JM, et al. p110gamma and p110delta phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity. 2007;27:214–27.
pubmed: 17723215
doi: 10.1016/j.immuni.2007.07.014
Saudemont A, Garçon F, Yadi H, Roche-Molina M, Kim N, Segonds-Pichon A, et al. p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci USA. 2009;106:5795–800.
pubmed: 19297623
pmcid: 2667007
doi: 10.1073/pnas.0808594106
Davis RJ, Moore EC, Clavijo PE, Friedman J, Cash H, Chen Z, et al. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kdelta/gamma. Cancer Res. 2017;77:2607–2619.
pubmed: 28364000
pmcid: 5466078
doi: 10.1158/0008-5472.CAN-16-2534
Abu-Eid R, Samara RN, Ozbun L, Abdalla MY, Berzofsky JA, Friedman KM, et al. Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol. Res. 2014;2:1080–9.
pubmed: 25080445
pmcid: 4221428
doi: 10.1158/2326-6066.CIR-14-0095
Chellappa S, Kushekhar K, Munthe LA, Tjønnfjord GE, Aandahl EM, Okkenhaug K, et al. The PI3K p110delta isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function. J. Immunol. 2019;202:1397–1405.
pubmed: 30692213
doi: 10.4049/jimmunol.1701703
Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, et al. Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Disco. 2011;1:222–35.
doi: 10.1158/2159-8290.CD-11-0098
Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539:112–117.
pubmed: 27595394
pmcid: 5340502
doi: 10.1038/nature19796
Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, et al. On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature. 2016;539:107–111.
pubmed: 27595393
pmcid: 5499381
doi: 10.1038/nature19795
Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36:867–874.
pubmed: 29257710
doi: 10.1200/JCO.2017.74.2627
Choueiri, TK, et al. Inhibition of hypoxia-inducible factor-2alpha in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med.2021.
Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120:2699–714.
pubmed: 20644254
pmcid: 2912179
doi: 10.1172/JCI39506