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.

中文翻译：

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增强癌细胞中线粒体定位蛋白的免疫原性。


源自突变癌症蛋白的表位会引发强烈的抗肿瘤 T 细胞反应，这与部分患者的临床疗效相关。然而，尚不清楚突变蛋白的亚细胞定位是否影响 T 细胞启动的效率。为了解决这个问题，我们比较了 NY-ESO-1 和 OVA 位于细胞质或线粒体中的免疫原性。我们发现表达线粒体定位的 NY-ESO-1 和 OVA 蛋白的肿瘤在体内引起显着更高频率的抗原特异性 CD8+ T 细胞。我们还证明，这种更强的免疫反应取决于抗原蛋白的线粒体位置，与胞质定位蛋白相比，这有助于其稳态数量更高。与这些发现一致，我们表明注射从 B16 黑色素瘤细胞纯化的线粒体可以保护小鼠免受 B16 细胞的攻击，但不能保护不相关肿瘤的攻击。最后，我们通过证明 T 细胞对突变线粒体定位蛋白的特异性反应的存在，将这些发现扩展到癌症患者。这些发现强调了优先考虑源自线粒体定位突变蛋白的表位作为癌症疫苗接种策略的目标的效用。