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.

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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

Author notes

    • Donna L Herber
    •  & Wei Cao

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.

    • Donna L Herber
    • , Wei Cao
    • , Yulia Nefedova
    • , Sergey V Novitskiy
    • , Srinivas Nagaraj
    • , Alex Corzo
    • , Hyun-Il Cho
    • , Esteban Celis
    • , Brianna Lennox
    •  & Dmitry I Gabrilovich
  2. Center for Free Radical and Antioxidant Health, Department of Environmental Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Vladimir A Tyurin
    •  & Valerian E Kagan
  3. Department of Molecular Medicine, University of South Florida, Tampa, Florida, USA.

    • Esteban Celis
    •  & Dmitry I Gabrilovich
  4. Department of Immunopathology, Imperial College London, London, UK.

    • Stella C Knight
  5. Department of Otolaryngology, University of South Florida, Tampa, Florida, USA.

    • Tapan Padhya
    • , Thomas V McCaffrey
    •  & Judith C McCaffrey
  6. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Scott Antonia
  7. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Mayer Fishman
  8. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Robert L Ferris

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dmitry I Gabrilovich.

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DOI

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

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