The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

Cellular and Molecular Immunology

Volumn 15, Issue 5, 2018, Pages 421-427

  Mohamed, Eslam ^a   Al Khami, Amir A ^b   Rodriguez, Paulo C ^a  

^a H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

^b LOUISIANA STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

immune suppression; metabolic reprogramming; myeloid cells; Tumor microenvironment

Indexed keywords

ADULT; ARTICLE; BEHAVIOR; BONE MARROW CELL; CANCER CELL; CELL MIGRATION; CELL PROLIFERATION; ENERGY METABOLISM; HUMAN; HUMAN CELL; IMMUNOCOMPETENT CELL; IMMUNOSUPPRESSIVE TREATMENT; LANDSCAPE; NUTRIENT; SIGNAL TRANSDUCTION; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; ANIMAL; GLYCOLYSIS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; LIPID METABOLISM; METABOLISM; NEOPLASM; PATHOLOGY;

ANIMALS; GLYCOLYSIS; HUMANS; IMMUNE TOLERANCE; LIPID METABOLISM; MYELOID CELLS; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 85044279191     PISSN: 16727681     EISSN: None     Source Type: Journal    
DOI: 10.1038/s41423-018-0001-7     Document Type: Review

References (121)

1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)
2. Ward, P. S. & Thompson, C. B. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21, 297–308 (2012)
3. Boroughs, L. K. & DeBerardinis, R. J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17, 351–359 (2015)
4. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015)
5. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014)
6. Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012)
7. Husain, Z., Huang, Y., Seth, P. & Sukhatme, V. P. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J. Immunol. 191, 1486–1495 (2013)
8. Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008)
9. Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010)
10. Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013)
11. DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011)
12. Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015)
13. Biswas, S. K. & Mantovani, A. Orchestration of metabolism by macrophages. Cell Metab. 15, 432–437 (2012)
14. Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017)
15. Mills, E. L., Kelly, B. & O’Neill, L. A. J. Mitochondria are the powerhouses of immunity. Nat. Immunol. 18, 488–498 (2017)
16. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927)
17. Moreira, J. D. et al. The redox status of cancer cells supports mechanisms behind the Warburg effect. Metabolites 6, pii: E33 (2016)
18. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009)
19. Keibler, M. A. et al. Metabolic requirements for cancer cell proliferation. Cancer Metab. 4, 16 (2016)
20. Al-Khami, A. A., Rodriguez, P. C. & Ochoa, A. C. Metabolic reprogramming of myeloid-derived suppressor cells (MDSC) in cancer. Oncoimmunology 5, e1200771 (2016)
21. Al-Khami, A. A., Rodriguez, P. C. & Ochoa, A. C. Energy metabolic pathways control the fate and function of myeloid immune cells. J. Leukoc. Biol. 102, 369–380 (2017)
22. Biswas, S. K., Allavena, P. & Mantovani, A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin. Immunopathol. 35, 585–600 (2013)
23. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010)
24. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013)
25. Rodriguez-Prados, J. C. et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185, 605–614 (2010)
26. Biswas, S. K., Sica, A. & Lewis, C. E. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J. Immunol. 180, 2011–2017 (2008)
27. Burke, B. et al. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am. J. Pathol. 163, 1233–1243 (2003)
28. Everts, B. et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422–1431 (2012)
29. Vats, D. et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell. Metab. 4, 13–24 (2006)
30. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014)
31. Huang, S. C. et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45, 817–830 (2016)
32. Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014)
33. Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016)
34. Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 597 (2017)
35. Pearce, E. J. & Everts, B. Dendritic cell metabolism. Nat. Rev. Immunol. 15, 18–29 (2015)
36. Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323–332 (2014)
37. Jantsch, J. et al. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 180, 4697–4705 (2008)
38. Scarlett, U. K. et al. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J. Exp. Med. 209, 495–506 (2012)
39. Gottfried, E. et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021 (2006)
40. Novitskiy, S. V. et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112, 1822–1831 (2008)
41. Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 16, 880–886 (2010)
42. Cubillos-Ruiz, J. R., Bettigole, S. E. & Glimcher, L. H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 168, 692–706 (2017)
43. Jun, H. S., Weinstein, D. A., Lee, Y. M., Mansfield, B. C. & Chou, J. Y. Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib. Blood 123, 2843–2853 (2014)
44. Rodriguez-Espinosa, O., Rojas-Espinosa, O., Moreno-Altamirano, M. M., Lopez-Villegas, E. O. & Sanchez-Garcia, F. J. Metabolic requirements for neutrophil extracellular traps formation. Immunology 145, 213–224 (2015)
45. Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011)
46. Singhal, S. et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 30, 120–135 (2016)
47. Condamine, T. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, pii: aaf8943 (2016)
48. Goffaux, G., Hammami, I. & Jolicoeur, M. A dynamic metabolic flux analysis of myeloid-derived suppressor cells confirms immunosuppression-related metabolic plasticity. Sci. Rep. 7, 9850 (2017)
49. Jian, S. L. et al. Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis. Cell Death Dis. 8, e2779 (2017)
50. Liu, G. et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1alpha-dependent glycolysis. Cancer Res. 74, 727–737 (2014)
51. Lu Y. et al. Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1alpha-dependent glycolysis. Cell. Mol. Immunol. (2017). 10.1038/cmi.2017.5
52. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011)
53. Nomura, D. K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49–61 (2010)
54. Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013)
55. Gao, F. et al. Radiation-driven lipid accumulation and dendritic cell dysfunction in cancer. Sci. Rep. 5, 9613 (2015)
56. Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015)
57. Hossain, F. et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 3, 1236–1247 (2015)
58. Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014)
59. Al-Khami, A. A. et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. Oncoimmunology 6, e1344804 (2017)
60. Hammami, I. et al. Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models. BMC Cell Biol. 13, 18 (2012)
61. O’Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016)
62. O’Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013)
63. Galic, S. et al. Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J. Clin. Invest. 121, 4903–4915 (2011)
64. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011)
65. Toyama, E. Q. et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016)
66. Rabinovitch, R. C. et al. AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species. Cell Rep. 21, 1–9 (2017)
67. Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010)
68. Trikha, P. et al. Targeting myeloid-derived suppressor cells using a novel adenosine monophosphate-activated protein kinase (AMPK) activator. Oncoimmunology 5, e1214787 (2016)
69. Kim, S. H. et al. Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. J. Invest. Dermatol. 137, 1740–1748 (2017)
70. Rong, Y. et al. Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2. Sci. Rep. 6, 23824 (2016)
71. Steinberg, G. R. & Schertzer, J. D. AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunol. Cell. Biol. 92, 340–345 (2014)
72. Sag, D., Carling, D., Stout, R. D. & Suttles, J. Adenosine 5’-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633–8641 (2008)
73. Park, S. Y. et al. SIRT1/adenosine monophosphate-activated protein kinase alpha signaling enhances macrophage polarization to an anti-inflammatory phenotype in rheumatoid arthritis. Front. Immunol. 8, 1135 (2017)
74. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015)
75. Rodriguez, P. C. et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med. 202, 931–939 (2005)
76. Obermajer, N., Muthuswamy, R., Odunsi, K., Edwards, R. P. & Kalinski, P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 71, 7463–7470 (2011)
77. Mao, Y. et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 73, 3877–3887 (2013)
78. Mao, Y. et al. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin. Cancer Res. 20, 4096–4106 (2014)
79. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9, 1269–1274 (2003)
80. Hsu, Y. L. et al. Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget 7, 27584–27598 (2016)
81. Munn, D. H. & Mellor, A. L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34, 137–143 (2013)
82. Rath, M., Muller, I., Kropf, P., Closs, E. I. & Munder, M. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front. Immunol. 5, 532 (2014)
83. Modolell, M., Corraliza, I. M., Link, F., Soler, G. & Eichmann, K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur. J. Immunol. 25, 1101–1104 (1995)
84. MacMicking, J., Xie, Q. W. & Nathan, C. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323–350 (1997)
85. Bogdan, C. Nitric oxide and the immune response. Nat. Immunol. 2, 907–916 (2001)
86. Albina, J. E. & Reichner, J. S. Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer Metastasis Rev. 17, 39–53 (1998)
87. Stuehr, D. J. & Nathan, C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med. 169, 1543–1555 (1989)
88. Marigo, I. et al. T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30, 651 (2016)
89. Albina, J. E., Mills, C. D., Henry, W. L. Jr. & Caldwell, M. D. Temporal expression of different pathways of 1-arginine metabolism in healing wounds. J. Immunol. 144, 3877–3880 (1990)
90. Chang, C. I., Liao, J. C. & Kuo, L. Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res. 61, 1100–1106 (2001)
91. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012)
92. Rodriguez, P. C. & Ochoa, A. C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol. Rev. 222, 180–191 (2008)
93. Rodriguez, P. C. et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 64, 5839–5849 (2004)
94. Zea, A. H. et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048 (2005)
95. Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016). e13
96. Ferns, D. M. et al. Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival. Oncoimmunology 4, e981457 (2015)
97. Liu, H. et al. Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma. Sci. Rep. 6, 21319 (2016)
98. Choe, J. Y. et al. Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study. BMC Cancer 14, 335 (2014)
99. Munn, D. H. & Mellor, A. L. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 37, 193–207 (2016)
100. Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005)
101. Van de Velde, L. A., Gingras, S., Pelletier, S. & Murray, P. J. Issues with the specificity of immunological reagents for murine IDO1. Cell Metab. 23, 389–390 (2016)
102. Terness, P. et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J. Exp. Med. 196, 447–457 (2002)
103. Zaher, S. S., Germain, C., Fu, H., Larkin, D. F. & George, A. J. 3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival. Invest. Ophthalmol. Vis. Sci. 52, 2640–2648 (2011)
104. Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010)
105. Munn, D. H. et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290 (2004)
106. Sharma, M. D. et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 2570–2582 (2007)
107. Holmgaard, R. B. et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 13, 412–424 (2015)
108. Yu, J. et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J. Immunol. 190, 3783–3797 (2013)
109. Schafer, C. C. et al. Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment. Oncotarget 7, 75407–75424 (2016)
110. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P. & Kalinski, P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118, 5498–5505 (2011)
111. Jitschin, R. et al. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood 124, 750–760 (2014)
112. Yu, J. et al. Noncanonical NF-kappaB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer. J. Immunol. 193, 2574–2586 (2014)
113. Smith, C. et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2, 722–735 (2012)
114. Liu, H. et al. GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Mol. Cell. Biol. 34, 428–438 (2014)
115. Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433 (2010)
116. Mazurek, S. & Eigenbrodt, E. The tumor metabolome. Anticancer Res. 23, 1149–1154 (2003)
117. Mates, J. M., Perez-Gomez, C., Nunez de Castro, I., Asenjo, M. & Marquez, J. Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int. J. Biochem. Cell. Biol. 34, 439–458 (2002)
118. Droge, W., Eck, H. P., Betzler, M. & Naher, H. Elevated plasma glutamate levels in colorectal carcinoma patients and in patients with acquired immunodeficiency syndrome (AIDS). Immunobiology 174, 473–479 (1987)
119. Gregory M. A. et al. Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia. Exp. Hematol. 58, 52–58 (2017)
120. Emadi, A. et al. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp. Hematol. 42, 247–251 (2014)
121. Jacque, N. et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood 126, 1346–1356 (2015)