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

Author

Listed:
  • Filippo Veglia

    (The Wistar Institute)

  • Vladimir A. Tyurin

    (University of Pittsburgh)

  • Dariush Mohammadyani

    (University of Pittsburgh
    Johns Hopkins University)

  • Maria Blasi

    (Duke University Medical Center)

  • Elizabeth K. Duperret

    (The Wistar Institute
    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
    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)

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.

Suggested Citation

  • Filippo Veglia & Vladimir A. Tyurin & Dariush Mohammadyani & Maria Blasi & Elizabeth K. Duperret & Laxminarasimha Donthireddy & Ayumi Hashimoto & Alexandr Kapralov & Andrew Amoscato & Roberto Angelini, 2017. "Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02186-9
    DOI: 10.1038/s41467-017-02186-9
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    Cited by:

    1. Angela Criscuolo & Palina Nepachalovich & Diego Fernando Garcia-del Rio & Mike Lange & Zhixu Ni & Massimo Baroni & Gabriele Cruciani & Laura Goracci & Matthias Blüher & Maria Fedorova, 2022. "Analytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Elizabeth L. Hardaker & Emilio Sanseviero & Ankur Karmokar & Devon Taylor & Marta Milo & Chrysis Michaloglou & Adina Hughes & Mimi Mai & Matthew King & Anisha Solanki & Lukasz Magiera & Ricardo Miraga, 2024. "The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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