Abstract
During an immune response, leukocytes undergo major changes in growth and function that are tightly coupled to dynamic shifts in metabolic processes. Immunometabolism is an emerging field that investigates the interplay between immunological and metabolic processes. The immune system has a key role to play in controlling cancer initiation and progression. Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. In tumor microenvironment, immune cells collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus prompting tumorigenesis and resistance to treatments. Here, we summarize the latest insights into the metabolic reprogramming of immune cells in tumor microenvironment and their potential roles in tumor progression and metastasis. Manipulating metabolic remodeling and immune responses may provide an exciting new option for cancer immunotherapy.
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Jiang Y, Li Y, Zhu B (2015) T-cell exhaustion in the tumor microenvironment. Cell Death Dis 6:e1792
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Son J et al (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496(7443):101–105
Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41(3):211–218
DeBerardinis RJ et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20
Sukumar M, Roychoudhuri R, Restifo NP (2015) Nutrient competition: a new axis of tumor immunosuppression. Cell 162(6):1206–1208
Chang CH et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241
Ho PC et al (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162(6):1217–1228
Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11(2):81
Murray PJ, Rathmell J, Pearce E (2015) SnapShot: immunometabolism. Cell Metab 22(1):190–190. e1
Mantovani A et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555
Mantovani A et al (2004) Infiltration of tumours by macrophages and dendritic cells: tumour-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Novartis Found Symp 256:137–145. discussion 146-8, 259-69
Mills EL, et al (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell
Mills EL, O’Neill LA (2016) Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur J Immunol 46(1):13–21
Rodriguez-Prados JC et al (2010) Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 185(1):605–614
Tannahill GM et al (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496(7444):238–242
Lampropoulou V et al (2016) Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24(1):158–166
Quatromoni JG, Eruslanov E (2012) Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res 4(4):376–389
Rodriguez PC et al (2003) L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171(3):1232–1239
Nagaraj S et al (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13(7):828–835
Harlin H et al (2009) Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 69(7):3077–3085
Kelly B, O'Neill LA (2015) Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25(7):771–784
Kelly B et al (2015) Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1beta (IL-1beta) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J Biol Chem 290(33):20348–20359
Palsson-McDermott EM 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(1):65–80
Huang SC et al (2016) Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45(4):817–830
Pearce EJ, Everts B (2015) Dendritic cell metabolism. Nat Rev Immunol 15(1):18–29
Krawczyk CM et al (2010) Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115(23):4742–4749
Everts B et al (2012) Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120(7):1422–1431
Everts B et al (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol 15(4):323–332
Motz GT, Coukos G (2013) Deciphering and reversing tumor immune suppression. Immunity 39(1):61–73
Dong H, Bullock TN (2014) Metabolic influences that regulate dendritic cell function in tumors. Front Immunol 5:24
Sim WJ, Ahl PJ, Connolly JE (2016) Metabolism is central to Tolerogenic dendritic cell function. Mediat Inflamm 2016:2636701
Ferreira GB et al (2015) Vitamin D3 induces tolerance in human dendritic cells by activation of intracellular metabolic pathways. Cell Rep 10:711–725
Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13(4):225–238
Lagouge M et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109–1122
Zheng J et al (2012) Resveratrol improves insulin resistance of catch-up growth by increasing mitochondrial complexes and antioxidant function in skeletal muscle. Metabolism 61(7):954–965
Svajger U, Obermajer N, Jeras M (2010) Dendritic cells treated with resveratrol during differentiation from monocytes gain substantial tolerogenic properties upon activation. Immunology 129(4):525–535
Le Mercier I et al (2013) Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment. Cancer Res 73(15):4629–4640
Wu D et al (2016) Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 44(6):1325–1336
O’Neill LA, Pearce EJ (2016) Immunometabolism governs dendritic cell and macrophage function. J Exp Med 213(1):15–23
Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022
MacIver NJ, Michalek RD, Rathmell JC (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31:259–283
Yang W et al (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531(7596):651–655
Dustin ML (2016) Cancer immunotherapy: killers on sterols. Nature 531(7596):583–584
Kidani Y et al (2013) Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14(5):489–499
Chang CH et al (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153(6):1239–1251
Peng M et al (2016) Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354(6311):481–484
Bengsch B et al (2016) Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity 45(2):358–373
Scharping NE et al (2016) The tumor microenvironment represses T cell mitochondrial biogenesis to drive Intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45(2):374–388
Pauken KE et al (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354(6316):1160–1165
Balmer ML, Hess C (2016) Feeling worn out? PGC1alpha to the rescue for dysfunctional mitochondria in T cell exhaustion. Immunity 45(2):233–235
Pearce EL et al (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460(7251):103–107
Prlic M, Bevan MJ (2009) Immunology: a metabolic switch to memory. Nature 460(7251):41–42
Buck MD et al (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166(1):63–76
Geiger R et al (2016) L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167(3):829–842. e13
Wei J et al (2016) Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol 17(3):277–285
Zeng H et al (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490
Angelin A, et al (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab
Sukumar M et al (2016) Mitochondrial membrane potential identifies cells with enhanced Stemness for cellular therapy. Cell Metab 23(1):63–76
Schug ZT, Vande Voorde J, Gottlieb E (2016) The nurture of tumors can drive their metabolic phenotype. Cell Metab 23(3):391–392
Davidson SM et al (2016) Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab 23(3):517–528
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Wu, D. (2017). Innate and Adaptive Immune Cell Metabolism in Tumor Microenvironment. In: Li, B., Pan, F. (eds) Immune Metabolism in Health and Tumor. Advances in Experimental Medicine and Biology, vol 1011. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-1170-6_7
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DOI: https://doi.org/10.1007/978-94-024-1170-6_7
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