Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/13715
Enhanced Immunogenicity of Mitochondrial-Localized Proteins in Cancer Cells.
Prota, Gennaro | Gileadi, Uzi | Rei, Margarida | Lechuga-Vieco, Ana Victoria | Chen, Ji-Li | Galiani, Silvia | Bedard, Melissa | Lau, Vivian Wing Chong | Fanchi, Lorenzo F | Artibani, Mara | Hu, Zhiyuan | Gordon, Siamon | Rehwinkel, Jan | Enriquez, Jose Antonio CNIC | Ahmed, Ahmed A | Schumacher, Ton N | Cerundolo, Vincenzo
Cancer Immunol Res. 2020; 8(5):685-697
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 steady-state 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.
Animals | Antigens, Neoplasm | CD4-Positive T-Lymphocytes | CD8-Positive T-Lymphocytes | Cancer Vaccines | Cell Line, Tumor | Disease Models, Animal | Epitopes | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Transgenic | Mitochondrial Proteins | Neoplasms
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