Enhanced immunogenicity of mitochondrial-localized proteins in cancer cells A C

Gennaro Prota*, Uzi Gileadi, Margarida Rei, Ana Victoria Lechuga-Vieco, Ji Li Chen, Silvia Galiani, Melissa Bedard, Vivian Wing Chong Lau, Lorenzo F. Fanchi, Mara Artibani, Zhiyuan Hu, Siamon Gordon, Jan Rehwinkel, Jose A. Enríquez, Ahmed A. Ahmed, Ton N. Schumacher, Vincenzo Cerundolo

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

9 Scopus citations

Abstract

Epitopes derived from mutated cancer proteins elicit strong antitumor T-cell responses that correlate with clinical efficacy in a proportion of patients. However, it remains unclear whether the subcellular localization of mutated proteins influences the efficiency of T-cell priming. To address this question, we compared the immunogenicity of NY-ESO-1 and OVA localized either in the cytosol or in mitochondria. We showed that tumors expressing mitochondrial-localized NY-ESO-1 and OVA proteins elicit significantdly higher frequencies of antigen-specific CD8+ T cells in vivo. We also demonstrated that this stronger immune response is dependent on the mitochondrial location of the antigenic proteins, which contributes to their higher steadystate amount, compared with cytosolic localized proteins. Consistent with these findings, we showed that injection of mitochondria purified from B16 melanoma cells can protect mice from a challenge with B16 cells, but not with irrelevant tumors. Finally, we extended these findings to cancer patients by demonstrating the presence of T-cell responses specific for mutated mitochondrial-localized proteins. These findings highlight the utility of prioritizing epitopes derived from mitochondrial- localized mutated proteins as targets for cancer vaccination strategies.

Original languageEnglish
Pages (from-to)685-697
Number of pages13
JournalCancer Immunology Research
Volume8
Issue number5
DOIs
StatePublished - 03 2020

Bibliographical note

Publisher Copyright:
© 2020 American Association for Cancer Research.

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