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

doi:10.1038/s41467-017-02186-9

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

Oncology Research

Research output: Contribution to journal › Article › peer-review

183 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 language	English (US)
Article number	2122
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02186-9
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-02186-9

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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), Article 2122. https://doi.org/10.1038/s41467-017-02186-9

Veglia, F, Tyurin, VA, Mohammadyani, D, Blasi, M, Duperret, EK, Donthireddy, L, Hashimoto, A, Kapralov, A, Amoscato, A, Angelini, R, Patel, S, Alicea-Torres, K, Weiner, D, Murphy, ME, Klein-Seetharaman, J, Celis, E, Kagan, VE & Gabrilovich, DI 2017, 'Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer', Nature communications, vol. 8, no. 1, 2122. https://doi.org/10.1038/s41467-017-02186-9

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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.",

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AU - Kapralov, Alexandr

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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.

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

Abstract

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