Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lipid accumulation and dendritic cell dysfunction in cancer

Abstract

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Lipid levels in DCs from tumor-bearing mice.
Figure 2: Lipid level in DCs from individuals with cancer.
Figure 3: The mechanism of lipid accumulation in DCs.
Figure 4: Defective functional activity of DCs with high lipid content.
Figure 5: Antigen processing in lipid-laden DCs.
Figure 6: Effects of pharmacological regulation of lipid levels on DC function in cancer.

Similar content being viewed by others

References

  1. Gabrilovich, D.I. The mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 4, 941–952 (2004).

    Article  CAS  Google Scholar 

  2. Shurin, M. & Chatta, G. Immunobiology of dendritic cells in cancer. in Tumor-induced immune suppression. Mechanisms and theraputic reversal. (eds. Gabrilovich, D.I. and Hurwitz, A.) 101–130 (Springer, New York, 2008).

  3. Calder, P.C. & Burdge, G.C. Fattty acids. in Bioactive lipids (eds. Nicolaou, A. & Kokotos, G.) 1–36 (Bridgewater: The Oily Press, 2004).

  4. Shaikh, S.R. & Edidin, M. Polyunsaturated fatty acids, membrane organization, T cells and antigen presentation. Am. J. Clin. Nutr. 84, 1277–1289 (2006).

    Article  CAS  Google Scholar 

  5. Knight, S.C. Specialized perinodal fat fuels and fashions immunity. Immunity 28, 135–138 (2008).

    Article  CAS  Google Scholar 

  6. Sanderson, P., MacPherson, G.G., Jenkins, C.H. & Calder, P.C. Dietary fish oil diminishes the antigen presentation activity of rat dendritic cells. J. Leukoc. Biol. 62, 771–777 (1997).

    Article  CAS  Google Scholar 

  7. Touitou, E., Godin, B., Karl, Y., Bujanover, S. & Becker, Y. Oleic acid, a skin penetration enhancer, affects Langerhans cells and corneocytes. J. Control. Release 80, 1–7 (2002).

    Article  CAS  Google Scholar 

  8. Säemann, M.D. et al. Bacterial metabolite interference with maturation of human monocyte-derived dendritic cells. J. Leukoc. Biol. 71, 238–246 (2002).

    PubMed  Google Scholar 

  9. Zeyda, M. et al. Polyunsaturated fatty acids block dendritic cell activation and function independently of NF-κB activation. J. Biol. Chem. 280, 14293–14301 (2005).

    Article  CAS  Google Scholar 

  10. Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C.N. & Sher, A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat. Immunol. 3, 76–82 (2002).

    Article  CAS  Google Scholar 

  11. Weatherill, A.R. et al. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4. J. Immunol. 174, 5390–5397 (2005).

    Article  CAS  Google Scholar 

  12. Shamshiev, A.T. et al. Dyslipidemia inhibits Toll-like receptor–induced activation of CD8α-negative dendritic cells and protective Th1 type immunity. J. Exp. Med. 204, 441–452 (2007).

    Article  CAS  Google Scholar 

  13. Angeli, V. et al. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity 21, 561–574 (2004).

    Article  CAS  Google Scholar 

  14. Packard, R.R. et al. CD11c+ dendritic cells maintain antigen processing, presentation capabilities and CD4+ T cell priming efficacy under hypercholesterolemic conditions associated with atherosclerosis. Circ. Res. 103, 965–973 (2008).

    Article  CAS  Google Scholar 

  15. Perrot, I. et al. Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J. Immunol. 178, 2763–2769 (2007).

    Article  CAS  Google Scholar 

  16. Halvorson, D.L. & McCune, S.A. Inhibition of fatty acid synthesis in isolated adipocytes by 5-(tetradecyloxy)-2-furoic acid. Lipids 19, 851–856 (1984).

    Article  CAS  Google Scholar 

  17. Nagaraj, S. et al. Dendritic cell–based full-length survivin vaccine in treatment of experimental tumors. J. Immunother. 30, 169–179 (2007).

    Article  CAS  Google Scholar 

  18. de Winther, M.P., van Dijk, K.W., Havekes, L.M. & Hofker, M.H. Macrophage scavenger receptor class A: a multifunctional receptor in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 20, 290–297 (2000).

    Article  CAS  Google Scholar 

  19. Peiser, L., Mukhopadhyay, S. & Gordon, S. Scavenger receptors in innate immunity. Curr. Opin. Immunol. 14, 123–128 (2002).

    Article  CAS  Google Scholar 

  20. Husemann, J., Loike, J.D., Anankov, R., Febbraio, M. & Silverstein, S.C. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, 195–205 (2002).

    Article  Google Scholar 

  21. Hagemann, T. et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol. 176, 5023–5032 (2006).

    Article  CAS  Google Scholar 

  22. Becker, M., Cotena, A., Gordon, S. & Platt, N. Expression of the class A macrophage scavenger receptor on specific subpopulations of murine dendritic cells limits their endotoxin response. Eur. J. Immunol. 36, 950–960 (2006).

    Article  CAS  Google Scholar 

  23. Jin, J.O. et al. Ligand of scavenger receptor class A indirectly induces maturation of human blood dendritic cells via production of tumor necrosis factor-alpha. Blood 113, 5839–5847 (2009).

    Article  CAS  Google Scholar 

  24. Delimaris, I. et al. Oxidized LDL, serum oxidizability and serum lipid levels in patients with breast or ovarian cancer. Clin. Biochem. 40, 1129–1134 (2007).

    Article  CAS  Google Scholar 

  25. Motta, M. et al. Antibodies against ox-LDL serum levels in patients with hepatocellular carcinoma. Panminerva Med. 45, 69–73 (2003).

    CAS  PubMed  Google Scholar 

  26. Youn, J.I., Nagaraj, S., Collazo, M. & Gabrilovich, D.I. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 181, 5791–5802 (2008).

    Article  CAS  Google Scholar 

  27. Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  28. Barnden, M.J., Allison, J., Heath, W.R. & Carbone, F.R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    Article  CAS  Google Scholar 

  29. Nefedova, Y. et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464–474 (2004).

    Article  CAS  Google Scholar 

  30. Nefedova, Y., Cheng, P., Alsina, M., Dalton, W.S. & Gabrilovich, D.I. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 103, 3503–3510 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health grant 1R21AI070598 to D.I.G., National Institutes of Health grants HL70755, HL094488 and OH008282 to V.E.K. and, in part, by the flow cytometry core of H. Lee Moffitt Cancer Center. Poly-IC was provided by A. Salazar (Oncovir).

Author information

Authors and Affiliations

Authors

Contributions

D.L.H. performed initial experiments and participated in the writing of the paper; W.C., Y.N., S.V.N., S.N., A.C. and B.L. performed experiments investigating the mechanism and immunological consequences of lipid accumulation in DCs and analyzed the data; V.E.K. and V.A.T. designed and performed experiments with mass spectrometry analysis of lipid content, analyzed the data and participated in writing the paper; E.C. and H.-I.C. designed and performed experiments with B16F10 model and analyzed the data; S.C.K. participated in the design of the original experiments and participated in writing the paper; T.P., T.V.M., J.C.M. and S.A. participated in experiments evaluating human samples; M.F. and R.L.F. participated in experiments evaluating human samples and participated in writing the paper; D.I.G. designed the study, analyzed the data and wrote the paper.

Corresponding author

Correspondence to Dmitry I Gabrilovich.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Methods and Supplementary Discussion (PDF 486 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herber, D., Cao, W., Nefedova, Y. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med 16, 880–886 (2010). https://doi.org/10.1038/nm.2172

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2172

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer