Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer

Filippo Veglia, Vladimir A. Tyurin, Dariush Mohammadyani, Maria Blasi, Elizabeth K. Duperret, Laxminarasimha Donthireddy, Ayumi Hashimoto, Alexandr Kapralov, Andrew Amoscato, Roberto Angelini, Sima Patel, Kevin Alicea-Torres, David Weiner, Maureen E. Murphy, Judith Klein-Seetharaman, Esteban Celis, Valerian E. Kagan, Dmitry I. Gabrilovich

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired cross-presentation in DCs is largely associated with defect in trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues.

Original languageEnglish (US)
Article number2122
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Veglia, F., Tyurin, V. A., Mohammadyani, D., Blasi, M., Duperret, E. K., Donthireddy, L., Hashimoto, A., Kapralov, A., Amoscato, A., Angelini, R., Patel, S., Alicea-Torres, K., Weiner, D., Murphy, M. E., Klein-Seetharaman, J., Celis, E., Kagan, V. E., & Gabrilovich, D. I. (2017). Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Nature communications, 8(1), [2122]. https://doi.org/10.1038/s41467-017-02186-9