TY - JOUR
T1 - Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer
AU - Veglia, Filippo
AU - Tyurin, Vladimir A.
AU - Mohammadyani, Dariush
AU - Blasi, Maria
AU - Duperret, Elizabeth K.
AU - Donthireddy, Laxminarasimha
AU - Hashimoto, Ayumi
AU - Kapralov, Alexandr
AU - Amoscato, Andrew
AU - Angelini, Roberto
AU - Patel, Sima
AU - Alicea-Torres, Kevin
AU - Weiner, David
AU - Murphy, Maureen E.
AU - Klein-Seetharaman, Judith
AU - Celis, Esteban
AU - Kagan, Valerian E.
AU - Gabrilovich, Dmitry I.
N1 - Funding Information:
This work was supported by NIH grant CA165065 to D.I.G. and V.E.K. as well as flow cytometry and mouse cores of the Wistar Institute. D.I.G. was supported by Davis Family Professorship. We thank Dr. S. Hensley (University of Pennsylvania) for providing us with FLU virus and Frederick Keeney (Imaging Facility, Wistar Institute for helping with confocal microscopy analysis.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-02186-9
DO - 10.1038/s41467-017-02186-9
M3 - Article
C2 - 29242535
AN - SCOPUS:85038836958
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2122
ER -