文章：

肿瘤抗原优先来源于黑色素瘤和非小细胞肺癌中未突变的基因组序列

Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer 

原文发布日期：2025-05-22 

英文摘要：

Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.

 摘要翻译：

黑色素瘤和非小细胞肺癌（NSCLC）呈现出异常高的突变负担。因此，在这两种癌症中，免疫治疗主要针对可能由非同义突变产生的肿瘤抗原（TAs）。通过全面的组分蛋白和基因组分析，我们鉴定出皮肤黑色素瘤中有589个TAs（n=505），非小细胞肺癌中有90个TAs（n=90）。在这之中，只有1%来自突变序列，这可归因于大部分非同义突变RNA表达低，并且它们位于主要与MHC I类抗原相关肽生成不活跃的基因组区域。相比之下，其余99%的TAs来源于未突变但特定于癌症的基因序列（异常表达肿瘤特异性抗原，aeTSAs；n=220），在癌症中高度过表达（肿瘤相关抗原，TAAs；n=165）或特定于细胞起源 lineage（lineage-specific antigens, LSAs；n=198）。aeTSAs的表达通过组分调控进行调控，并且大多数由非典型基因序列编码。这些aeTSAs在样本间共享，具有免疫活性并可能解释了先前研究中观察到的对免疫切块阻断治疗响应的支持其对多种癌症免疫靶向治疗的可能性。

 原文链接：

https://www.nature.com/articles/s43018-025-00979-2