Tumor-associated myeloid cells: new understandings on their metabolic regulation and their influence in cancer immunotherapy

FEBS Journal

Volumn 285, Issue 4, 2018, Pages 717-733

  Porta, Chiara ^a   Sica, Antonio ^a,b   Riboldi, Elena ^a  

^a UNIVERSITY OF EASTERN PIEDMONT   (Italy)

^b HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

Author keywords

checkpoint inhibitors; immunometabolism; myeloid derived suppressor cells; tumor microenvironment; tumor associated macrophages

Indexed keywords

AMINO ACID METABOLISM; BIOLOGICAL ACTIVITY; BONE MARROW CELL; CANCER IMMUNOTHERAPY; CANCER INFILTRATION; CELL CYCLE CHECKPOINT; CELL DIFFERENTIATION; ENERGY METABOLISM; GENE EXPRESSION REGULATION; GENE INTERACTION; HUMAN; ICOSANOID METABOLISM; IMMUNOSUPPRESSIVE TREATMENT; IRON HOMEOSTASIS; METABOLIC REGULATION; NONHUMAN; NUCLEAR REPROGRAMMING; PRIORITY JOURNAL; REVIEW; THERAPY EFFECT; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; CHEMISTRY; DRUG EFFECT; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; NEOPLASM;

IMMUNOLOGICAL ANTINEOPLASTIC AGENT;

ANTINEOPLASTIC AGENTS, IMMUNOLOGICAL; HUMANS; IMMUNOTHERAPY; MYELOID CELLS; NEOPLASMS;

EID: 85032571602     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/febs.14288     Document Type: Review

References (140)

1. Sica A, Porta C, Morlacchi S, Banfi S, Strauss L, Rimoldi M, Totaro MG & Riboldi E (2012) Origin and functions of tumor-associated myeloid cells (TAMCs). Cancer Microenviron 5, 133–149.
2. Sica A & Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122, 787–795.
3. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T et al. (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20.
4. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In't Veld P, De Baetselier P et al. (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70, 5728–5739.
5. Gabrilovich DI (2017) Myeloid-derived suppressor cells. Cancer Immunol Res 5, 3–8.
6. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7, 12150.
7. Coffelt SB, Wellenstein MD & de Visser KE (2016) Neutrophils in cancer: neutral no more. Nat Rev Cancer 16, 431–446.
8. Biswas SK (2015) Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449.
9. Harjes U, Kalucka J & Carmeliet P (2016) Targeting fatty acid metabolism in cancer and endothelial cells. Crit Rev Oncol Hematol 97, 15–21.
10. Reina-Campos M, Moscat J & Diaz-Meco M (2017) Metabolism shapes the tumor microenvironment. Curr Opin Cell Biol 48, 47–53.
11. Lyssiotis CA & Kimmelman AC (2017) Metabolic interactions in the tumor microenvironment. Trends Cell Biol https://doi.org/10.1016/j.tcb.2017.06.003
12. Galvan-Pena S & O'Neill LA (2014) Metabolic reprograming in macrophage polarization. Front Immunol 5, 420.
13. Porta C, Riboldi E, Ippolito A & Sica A (2015) Molecular and epigenetic basis of macrophage polarized activation. Semin Immunol 27, 237–248.
14. Ganeshan K & Chawla A (2014) Metabolic regulation of immune responses. Annu Rev Immunol 32, 609–634.
15. O'Neill LA, Kishton RJ & Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16, 553–565.
16. Kumar V, Patel S, Tcyganov E & Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37, 208–220.
17. Recalcati S, Locati M & Cairo G (2012) Systemic and cellular consequences of macrophage control of iron metabolism. Semin Immunol 24, 393–398.
18. Jung M, Mertens C & Brune B (2015) Macrophage iron homeostasis and polarization in the context of cancer. Immunobiology 220, 295–304.
19. Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, Zammataro L, Girelli D & Cairo G (2010) Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 40, 824–835.
20. Mertens C, Akam EA, Rehwald C, Brune B, Tomat E & Jung M (2016) Intracellular iron chelation modulates the macrophage iron phenotype with consequences on tumor progression. PLoS One 11, e0166164.
21. Marques O, Porto G, Rema A, Faria F, Cruz Paula A, Gomez-Lazaro M, Silva P, Martins da Silva B & Lopes C (2016) Local iron homeostasis in the breast ductal carcinoma microenvironment. BMC Cancer 16, 187.
22. Jung M, Weigert A, Tausendschon M, Mora J, Oren B, Sola A, Hotter G, Muta T & Brune B (2012) Interleukin-10-induced neutrophil gelatinase-associated lipocalin production in macrophages with consequences for tumor growth. Mol Cell Biol 32, 3938–3948.
23. Deng R, Wang SM, Yin T, Ye TH, Shen GB, Li L, Zhao JY, Sang YX, Duan XG & Wei YQ (2013) Inhibition of tumor growth and alteration of associated macrophage cell type by an HO-1 inhibitor in breast carcinoma-bearing mice. Oncol Res 20, 473–482.
24. Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, Pajarinen JS, Nejadnik H, Goodman S, Moseley M et al. (2016) Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol 11, 986–994.
25. Modolell M, Corraliza IM, Link F, Soler G & Eichmann K (1995) 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.
26. Rath M, Muller I, Kropf P, Closs EI & Munder M (2014) Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol 5, 532.
27. Wei D, Richardson EL, Zhu K, Wang L, Le X, He Y, Huang S & Xie K (2003) Direct demonstration of negative regulation of tumor growth and metastasis by host-inducible nitric oxide synthase. Cancer Res 63, 3855–3859.
28. Weiss JM, Ridnour LA, Back T, Hussain SP, He P, Maciag AE, Keefer LK, Murphy WJ, Harris CC, Wink DA et al. (2010) Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J Exp Med 207, 2455–2467.
29. Simoes RL, De-Brito NM, Cunha-Costa H, Morandi V, Fierro IM, Roitt IM & Barja-Fidalgo C (2017) Lipoxin A4 selectively programs the profile of M2 tumor-associated macrophages which favour control of tumor progression. Int J Cancer 140, 346–357.
30. Sharda DR, Yu S, Ray M, Squadrito ML, De Palma M, Wynn TA, Morris SM Jr & Hankey PA (2011) Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J Immunol 187, 2181–2192.
31. Kusmartsev S & Gabrilovich DI (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55, 237–245.
32. Sica A & Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117, 1155–1166.
33. Lu G, Zhang R, Geng S, Peng L, Jayaraman P, Chen C, Xu F, Yang J, Li Q, Zheng H et al. (2015) Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6, 6676.
34. Vannini F, Kashfi K & Nath N (2015) The dual role of iNOS in cancer. Redox Biol 6, 334–343.
35. Fionda C, Abruzzese MP, Santoni A & Cippitelli M (2016) Immunoregulatory and effector activities of nitric oxide and reactive nitrogen species in cancer. Curr Med Chem 23, 2618–2636.
36. Cimen Bozkus C, Elzey BD, Crist SA, Ellies LG & Ratliff TL (2015) Expression of cationic amino acid transporter 2 is required for myeloid-derived suppressor cell-mediated control of T cell immunity. J Immunol 195, 5237–5250.
37. Srivastava MK, Sinha P, Clements VK, Rodriguez P & Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70, 68–77.
38. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, Yu W, Shen C, Liu J & Ren X (2013) 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.
39. Grohmann U & Bronte V (2010) Control of immune response by amino acid metabolism. Immunol Rev 236, 243–264.
40. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM et al. (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563.
41. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B et al. (2015) Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430.
42. Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, Di Conza G, Cheng WC, Chou CH, Vavakova M et al. (2017) Alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol 18, 985–994.
43. Mantovani A & Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22, 231–237.
44. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M & Bosca L (2010) Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 185, 605–614.
45. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ & Chawla A (2006) Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4, 13–24.
46. Huang SC, Everts B, Ivanova Y, O'Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O'Neill CM et al. (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15, 846–855.
47. Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, Knapp B, Haas R, Schmid JA, Jandl C et al. (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15, 813–826.
48. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS & Ghosh S (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–480.
49. Infantino V, Convertini P, Cucci L, Panaro MA, Di Noia MA, Calvello R, Palmieri F & Iacobazzi V (2011) The mitochondrial citrate carrier: a new player in inflammation. Biochem J 438, 433–436.
50. Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A et al. (2013) Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci USA 110, 7820–7825.
51. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH et al. (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242.
52. Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG et al. (2015) Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab 21, 65–80.
53. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A & Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744.
54. Moon JS, Lee S, Park MA, Siempos II, Haslip M, Lee PJ, Yun M, Kim CK, Howrylak J, Ryter SW et al. (2015) UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest 125, 665–680.
55. Odegaard JI & Chawla A (2008) Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 4, 619–626.
56. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B & Lee CH (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 7, 485–495.
57. Galic S, Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR, Izon D, Honeyman J, Chen ZP, van Denderen BJ et al. (2011) Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest 121, 4903–4915.
58. Chan KL, Pillon NJ, Sivaloganathan DM, Costford SR, Liu Z, Theret M, Chazaud B & Klip A (2015) Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J Biol Chem 290, 16979–16988.
59. Sag D, Carling D, Stout RD & Suttles J (2008) Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 181, 8633–8641.
60. Zhu YP, Brown JR, Sag D, Zhang L & Suttles J (2015) Adenosine 5′-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J Immunol 194, 584–594.
61. Mounier R, Theret M, Arnold L, Cuvellier S, Bultot L, Goransson O, Sanz N, Ferry A, Sakamoto K, Foretz M et al. (2013) AMPKalpha1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab 18, 251–264.
62. Tan Z, Xie N, Cui H, Moellering DR, Abraham E, Thannickal VJ & Liu G (2015) Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol 194, 6082–6089.
63. Malandrino MI, Fucho R, Weber M, Calderon-Dominguez M, Mir JF, Valcarcel L, Escote X, Gomez-Serrano M, Peral B, Salvado L et al. (2015) Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation. Am J Physiol Endocrinol Metab 308, E756–E769.
64. Nomura M, Liu J, Rovira II, Gonzalez-Hurtado E, Lee J, Wolfgang MJ & Finkel T (2016) Fatty acid oxidation in macrophage polarization. Nat Immunol 17, 216–217.
65. Van den Bossche J, O'Neill LA & Menon D (2017) Macrophage immunometabolism: where are we (going)? Trends Immunol 38, 395–406.
66. Liu D, Chang C, Lu N, Wang X, Lu Q, Ren X, Ren P, Zhao D, Wang L, Zhu Y et al. (2017) Comprehensive proteomics analysis reveals metabolic reprogramming of tumor-associated macrophages stimulated by the tumor microenvironment. J Proteome Res 16, 288–297.
67. Penny HL, Sieow JL, Adriani G, Yeap WH, See Chi Ee P, San Luis B, Lee B, Lee T, Mak SY, Ho YS et al. (2016) Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5, e1191731.
68. Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Perez R, Serneels J, Prenen H, Ghesquiere B, Carmeliet P & Mazzone M (2016) Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24, 701–715.
69. Lahmar Q, Keirsse J, Laoui D, Movahedi K, Van Overmeire E & Van Ginderachter JA (2016) Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment. Biochim Biophys Acta 1865, 23–34.
70. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721–732.
71. Lewis C & Murdoch C (2005) Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167, 627–635.
72. Goveia J, Stapor P & Carmeliet P (2014) Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease. EMBO Mol Med 6, 1105–1120.
73. Buck MD, Sowell RT, Kaech SM & Pearce EL (2017) Metabolic instruction of immunity. Cell 169, 570–586.
74. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K et al. (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24, 657–671.
75. Carmona-Fontaine C, Deforet M, Akkari L, Thompson CB, Joyce JA & Xavier JB (2017) Metabolic origins of spatial organization in the tumor microenvironment. Proc Natl Acad Sci USA 114, 2934–2939.
76. Ip WKE, Hoshi N, Shouval DS, Snapper S & Medzhitov R (2017) Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519.
77. Ouyang W, Rutz S, Crellin NK, Valdez PA & Hymowitz SG (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29, 71–109.
78. Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, Valle LD, Trillo-Tinoco J, Maj T, Zou W et al. (2015) Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res 3, 1236–1247.
79. Park J, Lee SE, Hur J, Hong EB, Choi JI, Yang JM, Kim JY, Kim YC, Cho HJ, Peters JM et al. (2015) M-CSF from cancer cells induces fatty acid synthase and PPARbeta/delta activation in tumor myeloid cells, leading to tumor progression. Cell Rep 10, 1614–1625.
80. Baardman J, Licht I, de Winther MP & Van den Bossche J (2015) Metabolic-epigenetic crosstalk in macrophage activation. Epigenomics 7, 1155–1164.
81. De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S et al. (2009) Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J 28, 3341–3352.
82. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G & Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130, 1083–1094.
83. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T et al. (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11, 936–944.
84. Van den Bossche J, Lamers WH, Koehler ES, Geuns JM, Alhonen L, Uimari A, Pirnes-Karhu S, Van Overmeire E, Morias Y, Brys L et al. (2012) Pivotal advance: arginase-1-independent polyamine production stimulates the expression of IL-4-induced alternatively activated macrophage markers while inhibiting LPS-induced expression of inflammatory genes. J Leukoc Biol 91, 685–699.
85. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR & Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080.
86. Fan J, Krautkramer KA, Feldman JL & Denu JM (2015) Metabolic regulation of histone post-translational modifications. ACS Chem Biol 10, 95–108.
87. Covarrubias AJ, Aksoylar HI, Yu J, Snyder NW, Worth AJ, Iyer SS, Wang J, Ben-Sahra I, Byles V, Polynne-Stapornkul T et al. (2016) Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife 5, e11612.
88. Chalkiadaki A & Guarente L (2015) The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 15, 608–624.
89. Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK & McCall CE (2016) Sirtuins link inflammation and metabolism. J Immunol Res 2016, 8167273.
90. Liu TF, Yoza BK, El Gazzar M, Vachharajani VT & McCall CE (2011) NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J Biol Chem 286, 9856–9864.
91. Liu TF, Vachharajani VT, Yoza BK & McCall CE (2012) NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 287, 25758–25769.
92. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12, 252–264.
93. Mantovani A, Marchesi F, Malesci A, Laghi L & Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14, 399–416.
94. Ostuni R, Kratochvill F, Murray PJ & Natoli G (2015) Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol 36, 229–239.
95. Tobin RP, Davis D, Jordan KR & McCarter MD (2017) The clinical evidence for targeting human myeloid-derived suppressor cells in cancer patients. J Leukoc Biol 102, 381–391.
96. Dyck L & Mills KHG (2017) Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol 47, 765–779.
97. Makkouk A & Weiner GJ (2015) Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res 75, 5–10.
98. Page DB, Postow MA, Callahan MK, Allison JP & Wolchok JD (2014) Immune modulation in cancer with antibodies. Annu Rev Med 65, 185–202.
99. Podojil JR & Miller SD (2017) Potential targeting of B7-H4 for the treatment of cancer. Immunol Rev 276, 40–51.
100. Matlung HL, Szilagyi K, Barclay NA & van den Berg TK (2017) The CD47-SIRPalpha signaling axis as an innate immune checkpoint in cancer. Immunol Rev 276, 145–164.
101. Akalu YT, Rothlin CV & Ghosh S (2017) TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev 276, 165–177.
102. Moran AE, Kovacsovics-Bankowski M & Weinberg AD (2013) The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 25, 230–237.
103. Noy R & Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61.
104. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, Gupta R, Tsai JM, Sinha R, Corey D et al. (2017) PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499.
105. Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9, eaal3604.
106. Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M & Korman AJ (2013) Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res 1, 32–42.
107. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD et al. (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210, 1695–1710.
108. Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P & Speiser DE (2015) Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci USA 112, 6140–6145.
109. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V & Chouaib S (2014) PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211, 781–790.
110. Geeraerts X, Bolli E, Fendt SM & Van Ginderachter JA (2017) Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol 8, 289.
111. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P et al. (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6, 6692.
112. Kim SH, Li M, Trousil S, Zhang Y, Pasca di Magliano M, Swanson KD & Zheng B (2017) Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. J Invest Dermatol 137, 1740–1748.
113. Scharping NE, Menk AV, Whetstone RD, Zeng X & Delgoffe GM (2017) Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res 5, 9–16.
114. Prima V, Kaliberova LN, Kaliberov S, Curiel DT & Kusmartsev S (2017) COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci USA 114, 1117–1122.
115. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B et al. (2014) Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111, 11774–11779.
116. Sica A & Strauss L (2017) Energy metabolism drives myeloid-derived suppressor cell differentiation and functions in pathology. J Leukoc Biol 102, 325–334.
117. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R & Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 117, 195–205.
118. Hu X, Wang Y, Hao LY, Liu X, Lesch CA, Sanchez BM, Wendling JM, Morgan RW, Aicher TD, Carter LL et al. (2015) Sterol metabolism controls T(H)17 differentiation by generating endogenous RORgamma agonists. Nat Chem Biol 11, 141–147.
119. Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, Totaro MG, Porta C, Anselmo A, Tartari S, Doni A et al. (2015) RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28, 253–269.
120. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA & Gabrilovich DI (2007) Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 67, 11021–11028.
121. Needham LA, Davidson AH, Bawden LJ, Belfield A, Bone EA, Brotherton DH, Bryant S, Charlton MH, Clark VL, Davies SJ et al. (2011) Drug targeting to monocytes and macrophages using esterase-sensitive chemical motifs. J Pharmacol Exp Ther 339, 132–142.
122. Bagalkot V, Badgeley MA, Kampfrath T, Deiuliis JA, Rajagopalan S & Maiseyeu A (2015) Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals. J Control Release 217, 243–255.
123. Silva VL & Al-Jamal WT (2017) Exploiting the cancer niche: tumor-associated macrophages and hypoxia as promising synergistic targets for nano-based therapy. J Control Release 253, 82–96.
124. Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, Winter PS, Liu X, Priyadharshini B, Slawinska ME et al. (2015) Metabolic programming and PDHK1 control CD4 + T cell subsets and inflammation. J Clin Invest 125, 194–207.
125. Zitvogel L, Pietrocola F & Kroemer G (2017) Nutrition, inflammation and cancer. Nat Immunol 18, 843–850.
126. Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M et al. (2016) Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146.
127. Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN & Scheck AC (2016) Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer 16, 310.
128. Mirsoian A, Bouchlaka MN, Sckisel GD, Chen M, Pai CC, Maverakis E, Spencer RG, Fishbein KW, Siddiqui S, Monjazeb AM et al. (2014) Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J Exp Med 211, 2373–2383.
129. Gorjifard S & Goldszmid RS (2016) Microbiota-myeloid cell crosstalk beyond the gut. J Leukoc Biol 100, 865–879.
130. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL et al. (2013) Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215.
131. Lakritz JR, Poutahidis T, Mirabal S, Varian BJ, Levkovich T, Ibrahim YM, Ward JM, Teng EC, Fisher B, Parry N et al. (2015) Gut bacteria require neutrophils to promote mammary tumorigenesis. Oncotarget 6, 9387–9396.
132. Rutkowski MR, Stephen TL, Svoronos N, Allegrezza MJ, Tesone AJ, Perales-Puchalt A, Brencicova E, Escovar-Fadul X, Nguyen JM, Cadungog MG et al. (2015) Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40.
133. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP et al. (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084.
134. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML et al. (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089.
135. Vacchelli E, Galluzzi L, Eggermont A, Galon J, Tartour E, Zitvogel L & Kroemer G (2012) Trial watch: immunostimulatory cytokines. Oncoimmunology 1, 493–506.
136. Zaidi MR & Merlino G (2011) The two faces of interferon-gamma in cancer. Clin Cancer Res 17, 6118–6124.
137. Miller CH, Maher SG & Young HA (2009) Clinical use of interferon-gamma. Ann N Y Acad Sci 1182, 69–79.
138. Kondo A, Yamashita T, Tamura H, Zhao W, Tsuji T, Shimizu M, Shinya E, Takahashi H, Tamada K, Chen L et al. (2010) Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes. Blood 116, 1124–1131.
139. Dawson MA & Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27.
140. Liu M, Zhou J, Chen Z & Cheng AS (2017) Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy. J Pathol 241, 10–24.