Tumor Immunity and Survival as a Function of Alternative Neopeptides in Human Cancer.
Tumor Immunity and Survival as a Function of Alternative Neopeptides in Human Cancer.
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DOI：
10.1158/2326-6066.cir-17-0559
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发表时间：
2018-03
影响因子：
10.1
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
--
作者：
Rech AJ;Balli D;Mantero A;Ishwaran H;Nathanson KL;Stanger BZ;Vonderheide RH
免疫系统通过T细胞依赖性识别肿瘤特异性抗原发挥抗肿瘤活性。虽然肿瘤新肽（来自体细胞突变的肽）的数量通常与免疫活性和存活率相关，但大多数经典定义的高亲和力新肽（CDN）不具有免疫原性，只有罕见的CDN与肿瘤排斥有关。因此，肿瘤抗原识别的规则仍然不完全清楚。在这里，我们分析了来自27种肿瘤类型的6，324名患者的新肽，免疫活性和临床结果。我们的特点是一类“替代定义的新肽”（ADN），这是预测结合MHC（I类或II类）的突变肽，相对于其非突变的对应物具有更高的亲和力。ADN是丰富的并且在分子上不同于CDN。ADN的负荷与肿瘤内T细胞反应和免疫抑制相关，ADN也是不同肿瘤类型患者生存率的强预测因子。这些结果扩展了具有潜在临床相关性的突变衍生的肿瘤抗原的谱。
The immune system exerts antitumor activity via T cell–dependent recognition of tumor-specific antigens. Although the number of tumor neopeptides—peptides derived from somatic mutations—often correlates with immune activity and survival, most classically defined high-affinity neopeptides (CDNs) are not immunogenic, and only rare CDNs have been linked to tumor rejection. Thus, the rules of tumor antigen recognition remain incompletely understood. Here, we analyzed neopeptides, immune activity, and clinical outcome from 6,324 patients across 27 tumor types. We characterized a class of “alternatively defined neopeptides” (ADNs), which are mutant peptides predicted to bind MHC (class I or II) with improved affinity relative to their nonmutated counterpart. ADNs are abundant and molecularly distinct from CDNs. The load of ADNs correlated with intratumoral T-cell responses and immune suppression, and ADNs were also strong predictors of patient survival across tumor types. These results expand the spectrum of mutation-derived tumor antigens with potential clinical relevance.