TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy

Cellular and Molecular Immunology

Volumn 15, Issue 5, 2018, Pages 428-437

  Huang, Lan ^a,b   Xu, Huaxi ^b   Peng, Guangyong ^a  

^a SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b JIANGSU UNIVERSITY   (China)

Author keywords

checkpoint blockade; immunotherapy; metabolic reprogramming; tumor microenvironment; warburg effect

Indexed keywords

6 PHOSPHOFRUCTO 2 KINASE; GLUCOSE TRANSPORTER 1; IMIQUIMOD; LACTATE DEHYDROGENASE; LOXORIBINE; PROTEIN SERINE KINASE; PYRUVATE DEHYDROGENASE KINASE; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 1; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR 9;

AMINO ACID METABOLISM; ARTICLE; CANCER IMMUNOTHERAPY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL ACTIVATION; CELL DIFFERENTIATION; CELL METABOLISM; CELL SURVIVAL; CPG ISLAND; DENDRITIC CELL; EFFECTOR CELL; ENERGY METABOLISM; ENZYME ACTIVITY; GENE EXPRESSION PROFILING; GLUCOSE METABOLISM; GLYCOLYSIS; HUMAN; HYPOXIA; IMMUNOGENICITY; IMMUNOREGULATION; LIPID METABOLISM; LIPOGENESIS; LYMPHOCYTE PROLIFERATION; NUCLEAR REPROGRAMMING; OXIDATIVE PHOSPHORYLATION; PHENOTYPE; PROTEIN BINDING; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; TLR SIGNALING; TLR8 SIGNALING; TUMOR MICROENVIRONMENT; ANIMAL; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; METABOLOME; NEOPLASM; PATHOLOGY;

ANIMALS; ENERGY METABOLISM; HUMANS; IMMUNOTHERAPY; METABOLOME; NEOPLASMS; TOLL-LIKE RECEPTORS; TUMOR MICROENVIRONMENT;

EID: 85050994830     PISSN: 16727681     EISSN: None     Source Type: Journal    
DOI: 10.1038/cmi.2018.4     Document Type: Article

References (123)

1. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23: 27–47.
2. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 2016; 41: 211–218.
3. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–1033.
4. 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: 1229–1241.
5. Lyssiotis CA, Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol 2017; 27: 863–875.
6. Reina-Campos M, Moscat J, Diaz-Meco M. Metabolism shapes the tumor microenvironment. Curr Opin Cell Biol 2017; 48: 47–53.
7. Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 2015; 25: 771–784.
8. Granucci F, Lutz MB, Zanoni I. The nature of activatory and tolerogenic dendritic cell-derived signal 2. Front Immunol 2014; 5: 42.
9. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 2015; 42: 419–430.
10. Arts RJ, Plantinga TS, Tuit S, Ulas T, Heinhuis B, Tesselaar M et al. Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages. Oncoimmunology 2016; 5: e1229725.
11. Penny HL, Sieow JL, Adriani G, Yeap WH, See Chi EeP, San Luis B et al. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 2016; 5: e1191731.
12. Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Perez R, Serneels J et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 2016; 24: 701–715.
13. Ramakrishnan R, Tyurin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol 2014; 192: 2920–2931.
14. Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med 2010; 16: 880–886.
15. 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.
16. Pearce EL2010Metabolism in T cell activation and differentiation. Curr Opin Immunol 22: 314–320.
17. Zeng H, Chi H. Metabolic control of regulatory T cell development and function. Trends Immunol 2015; 36: 3–12.
18. Newton R, Priyadharshini B, Turka LA. Immunometabolism of regulatory T cells. Nat Immunol 2016; 17: 618–625.
19. MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. 2013Annu Rev Immunol 31: 259–283.
20. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186: 3299–3303.
21. Chang CH, Curtis JD, Maggi LB Jr., Faubert B, Villarino AV, O'Sullivan D et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. 2013Cell 153: 1239–1251.
22. 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: 4479–4488.
23. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011; 208: 1367–1376.
24. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460: 103–107.
25. Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 2016; 166: 63–76.
26. Sukumar M, Roychoudhuri R, Restifo NP. Nutrient competition: a new axis of tumor immunosuppression. Cell 2015; 162: 1206–1208.
27. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 2016; 17: 95–103.
28. Xia H, Wang W, Crespo J, Kryczek I, Li W, Wei S et al. Suppression of FIP200 and autophagy by tumor-derived lactate promotes naive T cell apoptosis and affects tumor immunity. Sci Immunol 2017; 2 doi:10.1038/10.1126/sciimmunol.aan4631.
29. O'Sullivan D, Pearce EL. Targeting T cell metabolism for therapy. Trends Immunol 2015; 36: 71–80.
30. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010; 115: 4742–4749.
31. Pantel A, Teixeira A, Haddad E, Wood EG, Steinman RM, Longhi MP. Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol 2014; 12: e1001759.
32. Qualls JE, Subramanian C, Rafi W, Smith AM, Balouzian L, DeFreitas AA et al. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe 2012; 12: 313–323.
33. Geeraerts X, Bolli E, Fendt SM, Van Ginderachter JA. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol 2017; 8: 289.
34. Everts B, Pearce EJ. Metabolic control of dendritic cell activation and function: recent advances and clinical implications. Front Immunol 2014; 5: 203.
35. Dong H, Bullock TN. Metabolic influences that regulate dendritic cell function in tumors. Front Immunol 2014; 5: 24.
36. Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 2008; 27: 218–224.
37. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol 2010; 184: 1630–1641.
38. Ye J, Ma C, Hsueh EC, Dou J, Mo W, Liu S et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol Med 2014; 6: 1294–1311.
39. Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist 2008; 13: 859–875.
40. Ridnour LA, Cheng RY, Switzer CH, Heinecke JL, Ambs S, Glynn S et al. Molecular pathways: toll-like receptors in the tumor microenvironment—poor prognosis or new therapeutic opportunity. Clin Cancer Res 2013; 19: 1340–1346.
41. Yu L, Wang L, Chen S. Dual character of Toll-like receptor signaling: pro-tumorigenic effects and anti-tumor functions. Biochim Biophys Acta 2013; 1835: 144–154.
42. Veyrat M, Durand S, Classe M, Glavan TM, Oker N, Kapetanakis NI et al. Stimulation of the toll-like receptor 3 promotes metabolic reprogramming in head and neck carcinoma cells. Oncotarget 2016; 7: 82580–82593.
43. Karki K, Pande D, Negi R, Khanna S, Khanna RS, Khanna HD. Correlation of serum toll like receptor 9 and trace elements with lipid peroxidation in the patients of breast diseases. J Trace Elem Med Biol 2015; 30: 11–16.
44. Ye J, Peng G. Controlling T cell senescence in the tumor microenvironment for tumor immunotherapy. Oncoimmunology 2015; 4: e994398.
45. Kanzler H, Barrat FJ, Hessel EM, Coffman RL. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 2007; 13: 552–559.
46. Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 2010; 32: 692–702.
47. Shi G, Vistica BP, Nugent LF, Tan C, Wawrousek EF, Klinman DM et al. Differential involvement of Th1 and Th17 in pathogenic autoimmune processes triggered by different TLR ligands. J Immunol 2013; 191: 415–423.
48. Ye J, Wang Y, Liu X, Li L, Opejin A, Hsueh EC et al. TLR7 signaling regulates Th17 cells and autoimmunity: novel potential for autoimmune therapy. J Immunol 2017; 199: 941–954.
49. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005; 309: 1380–1384.
50. Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 2007; 13: 6947–6958.
51. Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity 2007; 27: 334–348.
52. Ye J, Huang X, Hsueh EC, Zhang Q, Ma C, Zhang Y et al. Human regulatory T cells induce T-lymphocyte senescence. Blood 2012; 120: 2021–2031.
53. Ye J, Ma C, Hsueh EC, Eickhoff CS, Zhang Y, Varvares MA et al. Tumor-derived gammadelta regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. J Immunol 2013; 190: 2403–2414.
54. Warburg O. On the origin of cancer cells. Science 1956; 123: 309–314.
55. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3: 177–185.
56. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem 2001; 276: 9519–9525.
57. Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 2016; 531: 110–113.
58. Wilde BR, Ayer DE. Interactions between Myc and MondoA transcription factors in metabolism and tumourigenesis. Br J Cancer 2015; 113: 1529–1533.
59. Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino acid transporters in cancer and their relevance to "glutamine addiction": novel targets for the design of a new class of anticancer drugs. Cancer Res 2015; 75: 1782–1788.
60. Yeung SJ, Pan J, Lee MH. Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol Life Sci 2008; 65: 3981–3999.
61. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 2016; 5: e189.
62. Gupta S, Roy A, Dwarakanath BS. Metabolic cooperation and competition in the tumor microenvironment: implications for therapy. Front Oncol 2017; 7: 68.
63. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 2008; 14: 5947–5952.
64. Sitkovsky M, Lukashev D. Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 2005; 5: 712–721.
65. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27: 5904–5912.
66. Keshari KR, Sriram R, Van Criekinge M, Wilson DM, Wang ZJ, Vigneron DB et al. Metabolic reprogramming and validation of hyperpolarized 13C lactate as a prostate cancer biomarker using a human prostate tissue slice culture bioreactor. Prostate 2013; 73: 1171–1181.
67. Rodrigues TB, Serrao EM, Kennedy BW, Hu DE, Kettunen MI, Brindle KM. Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose. Nat Med 2014; 20: 93–97.
68. Romero-Garcia S, Moreno-Altamirano MM, Prado-Garcia H, Sanchez-Garcia FJ. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol 2016; 7: 52.
69. 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: 1200–1209.
70. 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: 559–563.
71. 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. 2007Blood 109: 3812–3819.
72. 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.
73. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007; 204: 1303–1310.
74. Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skalhegg BS et al. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med 2001; 193: 497–507.
75. Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 2017; 18: 1332–1341.
76. Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 2013; 34: 137–143.
77. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41: 14–20.
78. Ferreira GB, Kleijwegt FS, Waelkens E, Lage K, Nikolic T, Hansen DA et al. Differential protein pathways in 1,25-dihydroxyvitamin d(3) and dexamethasone modulated tolerogenic human dendritic cells. J Proteome Res 2012; 11: 941–971.
79. Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce T(H)2 and tolerogenic responses. Nat Immunol 2010; 11: 647–655.
80. Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol 2010; 108: 111–165.
81. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013; 14: 500–508.
82. Marelli-Berg FM, Fu H, Mauro C. Molecular mechanisms of metabolic reprogramming in proliferating cells: implications for T-cell-mediated immunity. Immunology 2012; 136: 363–369.
83. Angela M, Endo Y, Asou HK, Yamamoto T, Tumes DJ, Tokuyama H et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARgamma directs early activation of T cells. Nat Commun 2016; 7: 13683.
84. 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: 871–882.
85. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 2014; 20: 1327–1333.
86. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 2013; 499: 485–490.
87. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011; 146: 772–784.
88. De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C 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: 1174–1184.
89. Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 2016; 44: 406–421.
90. 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: 1459–1466.
91. Glavan TM, Pavelic J. The exploitation of Toll-like receptor 3 signaling in cancer therapy. Curr Pharm Des 2014; 20: 6555–6564.
92. Liang X, Moseman EA, Farrar MA, Bachanova V, Weisdorf DJ, Blazar BR et al. Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood 2010; 115: 5041–5052.
93. Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 2012; 22: 466–478.
94. Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 2009; 457: 102–106.
95. Song EJ, Kang MJ, Kim YS, Kim SM, Lee SE, Kim CH et al. Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5. Int J Mol Med 2011; 28: 115–119.
96. Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 2005; 65: 5009–5014.
97. Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 2010; 120: 1285–1297.
98. Min R, Zun Z, Siyi L, Wenjun Y, Lizheng W, Chenping Z. Increased expression of Toll-like receptor-9 has close relation with tumour cell proliferation in oral squamous cell carcinoma. Arch Oral Biol 2011; 56: 877–884.
99. Wang EL, Qian ZR, Nakasono M, Tanahashi T, Yoshimoto K, Bando Y et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer 2010; 102: 908–915.
100. Cammarota R, Bertolini V, Pennesi G, Bucci EO, Gottardi O, Garlanda C et al. The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker. J Transl Med 2010; 8: 112.
101. Grimmig T, Moench R, Kreckel J, Haack S, Rueckert F, Rehder R et al. Toll like receptor 2, 4, and 9 signaling promotes autoregulative tumor cell growth and VEGF/PDGF expression in human pancreatic cancer. Int J Mol Sci 2016; 17: 2060.
102. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 2017; 170: 548–563 e16.
103. Ito H, Ando T, Arioka Y, Saito K, Seishima M. Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model. Immunology 2015; 144: 621–630.
104. Von Bubnoff D, Scheler M, Wilms H, Fimmers R, Bieber T. Identification of IDO-positive and IDO-negative human dendritic cells after activation by various proinflammatory stimuli. J Immunol 2011; 186: 6701–6709.
105. Manches O, Munn D, Fallahi A, Lifson J, Chaperot L, Plumas J et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest 2008; 118: 3431–3439.
106. Everts B, Amiel E, van der Windt GJ, Freitas TC, Chott R, Yarasheski KE et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 2012; 120: 1422–1431.
107. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 2013; 496: 238–242.
108. Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 2013; 4: 2834.
109. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol 2014; 15: 323–332.
110. Wu D, Sanin DE, Everts B, Chen Q, Qiu J, Buck MD et al. Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 2016; 44: 1325–1336.
111. Saas P, Varin A, Perruche S, Ceroi A. Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: potential ways to control these functions. F1000Res 2017; 6: 456.
112. Lachmandas E, Boutens L, Ratter JM, Hijmans A, Hooiveld GJ, Joosten LA et al. Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes. Nat Microbiol 2016; 2: 16246.
113. Sanin DE, Prendergast CT, Mountford AP. IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to genes involved in cell metabolism. J Immunol 2015; 195: 1218–1232.
114. Cottalorda A, Verschelde C, Marcais A, Tomkowiak M, Musette P, Uematsu S et al. TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation. Eur J Immunol 2006; 36: 1684–1693.
115. Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006; 116: 485–494.
116. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003; 299: 1033–1036.
117. Reynolds JM, Martinez GJ, Chung Y, Dong C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci USA 2012; 109: 13064–13069.
118. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 2003; 197: 403–411.
119. Salerno F, Guislain A, Cansever D, Wolkers MC. TLR-mediated innate production of IFN-gamma by CD8+ T cells is independent of glycolysis. J Immunol 2016; 196: 3695–3705.
120. Guha M. Anticancer TLR agonists on the ropes. Nat Rev Drug Discov 2012; 11: 503–505.
121. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6: 295–307.
122. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–264.
123. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 1996; 271: 32529–32537.