Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Lausanne, Switzerland.
Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Nat Biotechnol. 2022 Feb;40(2):175-188. doi: 10.1038/s41587-021-01038-8. Epub 2021 Oct 11.
The identification of actionable tumor antigens is indispensable for the development of several cancer immunotherapies, including T cell receptor-transduced T cells and patient-specific mRNA or peptide vaccines. Most known tumor antigens have been identified through extensive molecular characterization and are considered canonical if they derive from protein-coding regions of the genome. By eluting human leukocyte antigen-bound peptides from tumors and subjecting these to mass spectrometry analysis, the peptides can be identified by matching the resulting spectra against reference databases. Recently, mass-spectrometry-based immunopeptidomics has enabled the discovery of noncanonical antigens-antigens derived from sequences outside protein-coding regions or generated by noncanonical antigen-processing mechanisms. Coupled with transcriptomics and ribosome profiling, this method enables the identification of thousands of noncanonical peptides, of which a substantial fraction may be detected exclusively in tumors. Spectral matching against the immense noncanonical reference may generate false positives. However, sensitive mass spectrometry, analytical validation and advanced bioinformatics solutions are expected to uncover the full landscape of presented antigens and clinically relevant targets.
鉴定有作用的肿瘤抗原对于几种癌症免疫疗法的发展至关重要，包括 T 细胞受体转导的 T 细胞和患者特异性 mRNA 或肽疫苗。大多数已知的肿瘤抗原是通过广泛的分子特征鉴定出来的，如果它们来自基因组的蛋白编码区域，则被认为是规范的。通过从肿瘤中洗脱与人类白细胞抗原结合的肽，并对这些肽进行质谱分析，可以通过将得到的谱与参考数据库进行匹配来识别这些肽。最近，基于质谱的免疫肽组学已经能够发现非规范抗原——来自蛋白编码区域之外的序列或通过非规范抗原加工机制产生的抗原。结合转录组学和核糖体分析，这种方法可以识别数千种非规范肽，其中很大一部分可能仅在肿瘤中检测到。与庞大的非规范参考进行光谱匹配可能会产生假阳性。然而，敏感的质谱、分析验证和先进的生物信息学解决方案有望揭示呈现抗原和临床相关靶标的全貌。
