Metabolic regulation of immune responses: Therapeutic opportunities

Journal of Clinical Investigation

Volumn 126, Issue 6, 2016, Pages 2031-2039

  Assmann, Nadine ^a   Finlay, David K ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; ENZYME; GLUCOSE;

BIOSYNTHESIS; CELL FUNCTION; CELL METABOLISM; CELL SUBPOPULATION; HUMAN; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; LONGEVITY; METABOLIC REGULATION; METABOLITE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; BIOLOGICAL MODEL; CLASSIFICATION; CYTOLOGY; GLYCOLYSIS; IMMUNE SYSTEM; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; INFECTION; LYMPHOCYTE; METABOLISM; NEOPLASMS; OXIDATIVE PHOSPHORYLATION; PHYSIOLOGY; TUMOR MICROENVIRONMENT;

ADENOSINE TRIPHOSPHATE; ANIMALS; GLYCOLYSIS; HUMANS; IMMUNE SYSTEM; IMMUNOLOGIC MEMORY; INFECTION; LYMPHOCYTES; MODELS, IMMUNOLOGICAL; NEOPLASMS; OXIDATIVE PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84974555521     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI83005     Document Type: Review

References (114)

1. Donnelly RP, Finlay DK. Glucose, glycolysis lymphocyte responses. Mol Immunol. 2015; 68(2 pt C):513-519.
2. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033.
3. Wang R, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871-882.
4. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633-643.
5. Amiel E, et al. Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J Immunol. 2014;193(6):2821-2830.
6. Everts B, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvaraϵ supports the anabolic demands of dendritic cell activation. Nat Immunol. 2014;15(4):323-332.
7. Loftus RM, Finlay DK. Immunometabolism; cellular metabolism turns immune regulator. J Biol Chem. 2015;291(1):1-10.
8. Pearce EL, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009;460(7251):103-107.
9. + T cell memory and antitumor function. J Clin Invest. 2013;123(10):4479-4488.
10. Six E, et al. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages. Cell Death Dis. 2015;6:e1856.
11. Rivadeneira DB, et al. Survivin promotes oxidative phosphorylation, subcellular mitochondrial repositioning, and tumor cell invasion. Sci Signal. 2015;8(389):ra80.
12. Maryanovich M, et al. An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nat Commun. 2015;6:7901.
13. O'Sullivan D, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41(1):75-88.
14. Cui G, et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8(+) T cell longevity. Cell. 2015;161(4):750-761.
15. van der Windt GJ, et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc Natl Acad Sci U S A. 2013;110(35):14336-14341.
16. + T cells requires an immediate-early glycolytic switch. Nat Immunol. 2013;14(10):1064-1072.
17. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229(2):176-185.
18. Huang SC, et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol. 2014;15(9):846-855.
19. Siska PJ, Rathmell JC. T cell metabolic fitness in antitumor immunity. Trends Immunol. 2015;36(4):257-264.
20. Chang CH, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229-1241.
21. Ho PC, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015;162(6):1217-1228.
22. + T cells. J Exp Med. 2012;209(13):2441-2453.
23. Donnelly RP, et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol. 2014;193(9):4477-4484.
24. Chang CH, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153(6):1239-1251.
25. Vats D, et al. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab. 2006;4(1):13-24.
26. Tannahill GM, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013;496(7444):238-242.
27. Hirayama A, et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009;69(11):4918-4925.
28. Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625-2635.
29. Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013;10(3):230-252.
30. Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res. 2015;3(5):436-443.
31. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256-265.
32. Patsoukis N, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.
33. Benson DM Jr, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116(13):2286-2294.
34. Rajani K, et al. Combination therapy with reovirus anti-PD-1 blockade controls tumor growth through innate adaptive immune responses. Mol Ther. 2016;24(1):166-174.
35. Huang BY, et al. The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells. PLoS One. 2015;10(8):e0134715.
36. Robert C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
37. Postow MA, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017.
38. Topalian SL, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030.
39. Robert C, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532.
40. Garon EB, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028.
41. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.
42. Bronte V, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. 2005;201(8):1257-1268.
43. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196(4):459-468.
44. Munn DH, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281(5380):1191-1193.
45. Raber P, Ochoa AC, Rodriguez PC. Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest. 2012;41(6-7):614-634.
46. Fletcher M, et al. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015;75(2):275-283.
47. Bottcher M, et al. Mesenchymal stromal cells disrupt mTOR-signaling aerobic glycolysis during T-cell activation. Stem Cells. 2016;34(2):516-521.
48. 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. 2012;1(9):1460-1468.
49. + HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood. 2014;124(5):750-760.
50. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of Immune Responses by mTOR. Annu Rev Immunol. 2012;30:39-68.
51. Delgoffe GM, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295-303.
52. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280.
53. Karyampudi L, et al. Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Res. 2014;74(11):2974-2985.
54. Li B, VanRoey M, Wang C, Chen TH, Korman A, Jooss K. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor - secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res. 2009;15(5):1623-1634.
55. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73(12):3591-3603.
56. Melief CJ, van Hall T, Arens R, Ossendorp F, van der Burg SH. Therapeutic cancer vaccines. J Clin Invest. 2015;125(9):3401-3412.
57. Ninomiya S, et al. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood. 2015;125(25):3905-3916.
58. John LB, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19(20):5636-5646.
59. Sica A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18(5):349-355.
60. Ouimet M, et al. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest. 2015;125(12):4334-4348.
61. Freemerman AJ, et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem. 2014;289(11):7884-7896.
62. Haschemi A, et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 2012;15(6):813-826.
63. Jha AK, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419-430.
64. Everts B, et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood. 2012;120(7):1422-1431.
65. Vitko NP, Spahich NA, Richardson AR. Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus. MBio. 2015;6(2):e00045-15.
66. Tamune H, et al. Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am J Emerg Med. 2014;32(3):263-266.
67. Azevedo EP, et al. A metabolic shift towards pentose phosphate pathway is necessary for amyloid fibril- and phorbol 12-myristate 13-acetate-induced neutrophil extracellular trap (NET) formation. J Biol Chem. 2015;290(36):22174-22183.
68. McInturff AM, et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. Blood. 2012;120(15):3118-3125.
69. Rodriguez-Espinosa O, Rojas-Espinosa O, Moreno-Altamirano MM, Lopez-Villegas EO, Sanchez-Garcia FJ. Metabolic requirements for neutrophil extracellular traps formation. Immunology. 2015;145(2):213-224.
70. Ripoli M, et al. Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 α-mediated glycolytic adaptation. J Virol. 2010;84(1):647-660.
71. Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection. J Virol. 2011;85(4):1573-1580.
72. Thai M, et al. Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metab. 2014;19(4):694-701.
73. Sanchez EL, Lagunoff M. Viral activation of cellular metabolism. Virology. 2015;479-480:609-618.
74. Munger J, et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol. 2008;26(10):1179-1186.
75. Borregaard N, Herlin T. Energy metabolism of human neutrophils during phagocytosis. J Clin Invest. 1982;70(3):550-557.
76. Chambers JW, Maguire TG, Alwine JC. Glutamine metabolism is essential for human cytomegalovirus infection. J Virol. 2010;84(4):1867-1873.
77. Maciolek JA, Pasternak JA, Wilson HL. Metabolism of activated T lymphocytes. Curr Opin Immunol. 2014;27:60-74.
78. Radziewicz H, et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol. 2007;81(6):2545-2553.
79. Day CL, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350-354.
80. Urbani S, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol. 2006;80(22):11398-11403.
81. + T cells during acute HCV infection, irrespective of clinical outcome. J Virol. 2008;82(6):3154-3160.
82. Norris S, Coleman A, Kuri-Cervantes L, Bower M, Nelson M, Goodier MR. PD-1 expression on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral Immunol. 2012;25(4):329-332.
83. Wiesmayr S, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol. 2012;42(2):541-550.
84. Golden-Mason L, Klarquist J, Wahed AS, Rosen HR. Cutting edge: programmed death-1 expression is increased on immunocytes in chronic hepatitis C virus and predicts failure of response to antiviral therapy: race-dependent differences. J Immunol. 2008;180(6):3637-3641.
85. Dang EV, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772-784.
86. Shi LZ, et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367-1376.
87. Caro-Maldonado A, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014;192(8):3626-3636.
88. + T cell subsets. J Immunol. 2011;186(6):3299-3303.
89. Mascanfroni ID, et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat Med. 2015;21(6):638-646.
90. De Rosa V, et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. 2015;16(11):1174-1184.
91. Okoye I, et al. T cell metabolism. The protein LEM promotes CD8(+) T cell immunity through effects on mitochondrial respiration. Science. 2015;348(6238):995-1001.
92. Sena LA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38(2):225-236.
93. Gatza E, et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci Transl Med. 2011;3(67):67ra8.
94. + T cell metabolism reverses lupus. Sci Transl Med. 2015;7(274):274ra18.
95. Lee CF, et al. Preventing allograft rejection by targeting immune metabolism. Cell Rep. 2015;13(4):760-770.
96. Berod L, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 2014;20(11):1327-1333.
97. + T cells from lupus patients. J Clin Invest. 2014;124(2):712-724.
98. Kim JW, Dang CV. Multifaceted roles of glycolytic enzymes. Trends Biochem Sci. 2005;30(3):142-150.
99. Castello A, et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell. 2012;149(6):1393-1406.
100. Trevaskis NL, Charman WN, Porter CJ. Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation? Mol Pharm. 2010;7(6):2297-2309.
101. Ramishetti S, et al. Systemic gene silencing in primary T lymphocytes using targeted lipid nanoparticles. ACS Nano. 2015;9(7):6706-6716.
102. Caraux A, et al. Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood. 2006;107(3):994-1002.
103. + in FcaγR(CD16)-induced transcription and expression of lymphokine genes. J Exp Med. 1989;169(2):549-567.
104. Zhao E, et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol. 2016;17(1):95-103.
105. Israelsen WJ, Vander Heiden MG. Pyruvate kinase: function, regulation and role in cancer. Semin Cell Dev Biol. 2015;43:43-51.
106. Cheadle EJ, Gornall H, Baldan V, Hanson V, Hawkins RE, Gilham DE. CAR T cells: driving the road from the laboratory to the clinic. Immunol Rev. 2014;257(1):91-106.
107. Noman MZ, et al. Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. Cancer Res. 2015;75(18):3771-3787.
108. Noman MZ, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781-790.
109. Cramer T, et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell. 2003;112(5):645-657.
110. Doedens AL, et al. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res. 2010;70(19):7465-7475.
111. Mills E, O'Neill LA. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 2014;24(5):313-320.
112. Rubic T, et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol. 2008;9(11):1261-1269.
113. Cordes T, Michelucci A, Hiller K. Itaconic acid: the surprising role of an industrial compound as a mammalian antimicrobial metabolite. Annu Rev Nutr. 2015;35:451-473.
114. Mohanti BK, et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys. 1996;35(1):103-111.