Apavaloaei Anca, Zhao Qingchuan, Hesnard Leslie, Cahuzac Maxime, Durette Chantal, Larouche Jean-David, Hardy Marie-Pierre, Vincent Krystel, Brochu Sylvie, Laverdure Jean-Philippe, Lanoix Joël, Courcelles Mathieu, Gendron Patrick, Lajoie Mathieu, Ruiz Cuevas Maria Virginia, Kina Eralda, Perrault Julie, Humeau Juliette, Ehx Grégory, Lemieux Sébastien, Watson Ian R, Speiser Daniel E, Bassani-Sternberg Michal, Thibault Pierre, Perreault Claude
Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.
Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Nat Cancer. 2025 May 22. doi: 10.1038/s43018-025-00979-2.
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.
黑色素瘤和非小细胞肺癌（NSCLC）表现出异常高的突变负担。因此，这些癌症中的免疫靶向主要集中在预计源自非同义突变的肿瘤抗原（TA）上。通过全面的蛋白质基因组分析，我们在皮肤黑色素瘤（n = 505）和NSCLC（n = 90）中鉴定出589种TA。其中，只有1%源自突变序列，这是由于大多数非同义突变的RNA表达水平较低及其位于主要组织相容性复合体（MHC）I类相关肽产生能力不足的基因组区域之外。相比之下，99%的TA源自癌症特异性的未突变基因组序列（异常表达的肿瘤特异性抗原（aeTSA），n = 220）、在癌症中过表达的（肿瘤相关抗原（TAA），n = 165）或起源细胞谱系特异性的（谱系特异性抗原（LSA），n = 198）。aeTSA的表达受表观遗传调控，且大多数由非规范基因组序列编码。aeTSA在肿瘤样本中共享，具有免疫原性，并且可能有助于先前研究中观察到的对免疫检查点阻断的反应，支持它们在多种癌症中的免疫靶向作用。
