Prota, GennaroGileadi, UziRei, MargaridaLechuga-Vieco, Ana VictoriaChen, Ji-LiGaliani, SilviaBedard, MelissaLau, Vivian Wing ChongFanchi, Lorenzo FArtibani, MaraHu, ZhiyuanGordon, SiamonRehwinkel, JanEnriquez, Jose AntonioAhmed, Ahmed ASchumacher, Ton NCerundolo, Vincenzo2022-03-032022-03-032020-05Cancer Immunol Res. 2020; 8(5):685-697http://hdl.handle.net/20.500.12105/13715Epitopes 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/AnimalsAntigens, NeoplasmCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCancer VaccinesCell Line, TumorDisease Models, AnimalEpitopesMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMitochondrial ProteinsNeoplasmsAttribution-NonCommercial-NoDerivatives 4.0 Internacional3220531585685-69710.1158/2326-6066.CIR-19-04672326-6074Cancer immunology researchopen access