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 and Dmitry I. Gabrilovich ()
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Filippo Veglia: The Wistar Institute
Vladimir A. Tyurin: University of Pittsburgh
Dariush Mohammadyani: University of Pittsburgh
Maria Blasi: Duke University Medical Center
Elizabeth K. Duperret: The Wistar Institute
Laxminarasimha Donthireddy: The Wistar Institute
Ayumi Hashimoto: The Wistar Institute
Alexandr Kapralov: University of Pittsburgh
Andrew Amoscato: University of Pittsburgh
Roberto Angelini: University of Pittsburgh
Sima Patel: The Wistar Institute
Kevin Alicea-Torres: The Wistar Institute
David Weiner: The Wistar Institute
Maureen E. Murphy: The Wistar Institute
Judith Klein-Seetharaman: University of Pittsburgh
Esteban Celis: Georgia Cancer Center
Valerian E. Kagan: University of Pittsburgh
Dmitry I. Gabrilovich: The Wistar Institute

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02186-9

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