Skip to main content
SpringerLink
Log in

Innate and Adaptive Immune Cell Metabolism in Tumor Microenvironment

  • Chapter
  • First Online:
Immune Metabolism in Health and Tumor

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1011))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jiang Y, Li Y, Zhu B (2015) T-cell exhaustion in the tumor microenvironment. Cell Death Dis 6:e1792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  3. Son J et al (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496(7443):101–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41(3):211–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. DeBerardinis RJ et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20

    Article  CAS  PubMed  Google Scholar 

  6. Sukumar M, Roychoudhuri R, Restifo NP (2015) Nutrient competition: a new axis of tumor immunosuppression. Cell 162(6):1206–1208

    Article  CAS  PubMed  Google Scholar 

  7. Chang CH et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ho PC et al (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162(6):1217–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11(2):81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Murray PJ, Rathmell J, Pearce E (2015) SnapShot: immunometabolism. Cell Metab 22(1):190–190. e1

    Article  CAS  PubMed  Google Scholar 

  11. Mantovani A et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  PubMed  Google Scholar 

  13. Mills EL, et al (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell

    Google Scholar 

  14. Mills EL, O’Neill LA (2016) Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur J Immunol 46(1):13–21

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. Tannahill GM et al (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496(7444):238–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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

    PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Harlin H et al (2009) Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 69(7):3077–3085

    Article  CAS  PubMed  Google Scholar 

  22. Kelly B, O'Neill LA (2015) Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25(7):771–784

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. Pearce EJ, Everts B (2015) Dendritic cell metabolism. Nat Rev Immunol 15(1):18–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Krawczyk CM et al (2010) Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115(23):4742–4749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Everts B et al (2012) Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120(7):1422–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Motz GT, Coukos G (2013) Deciphering and reversing tumor immune suppression. Immunity 39(1):61–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dong H, Bullock TN (2014) Metabolic influences that regulate dendritic cell function in tumors. Front Immunol 5:24

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sim WJ, Ahl PJ, Connolly JE (2016) Metabolism is central to Tolerogenic dendritic cell function. Mediat Inflamm 2016:2636701

    Article  Google Scholar 

  33. Ferreira GB et al (2015) Vitamin D3 induces tolerance in human dendritic cells by activation of intracellular metabolic pathways. Cell Rep 10:711–725

    Article  CAS  Google Scholar 

  34. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13(4):225–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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

    Article  PubMed  Google Scholar 

  39. Wu D et al (2016) Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 44(6):1325–1336

    Article  CAS  PubMed  Google Scholar 

  40. O’Neill LA, Pearce EJ (2016) Immunometabolism governs dendritic cell and macrophage function. J Exp Med 213(1):15–23

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. MacIver NJ, Michalek RD, Rathmell JC (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31:259–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang W et al (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531(7596):651–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dustin ML (2016) Cancer immunotherapy: killers on sterols. Nature 531(7596):583–584

    Article  CAS  PubMed  Google Scholar 

  45. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chang CH et al (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153(6):1239–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Peng M et al (2016) Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354(6311):481–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pauken KE et al (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354(6316):1160–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Balmer ML, Hess C (2016) Feeling worn out? PGC1alpha to the rescue for dysfunctional mitochondria in T cell exhaustion. Immunity 45(2):233–235

    Article  CAS  PubMed  Google Scholar 

  52. Pearce EL et al (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460(7251):103–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Prlic M, Bevan MJ (2009) Immunology: a metabolic switch to memory. Nature 460(7251):41–42

    Article  CAS  PubMed  Google Scholar 

  54. Buck MD et al (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166(1):63–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Geiger R et al (2016) L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167(3):829–842. e13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zeng H et al (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Angelin A, et al (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab

    Google Scholar 

  59. Sukumar M et al (2016) Mitochondrial membrane potential identifies cells with enhanced Stemness for cellular therapy. Cell Metab 23(1):63–76

    Article  CAS  PubMed  Google Scholar 

  60. Schug ZT, Vande Voorde J, Gottlieb E (2016) The nurture of tumors can drive their metabolic phenotype. Cell Metab 23(3):391–392

    Article  CAS  PubMed  Google Scholar 

  61. Davidson SM et al (2016) Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab 23(3):517–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Shanghai, China

    Duojiao Wu

Authors
  1. Duojiao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Duojiao Wu .

Editor information

Editors and Affiliations

  1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University, Shanghai, China

    Bin Li

  2. School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Fan Pan

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

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

Download citation

Publish with us

Policies and ethics

Search

Navigation