Zhang Tengyi, Celiker Betul, Shao Yingkuan, Gai Jessica, Hill Mark, Wang Chunyu, Zheng Lei
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Clin Cancer Res. 2025 May 15;31(10):1956-1965. doi: 10.1158/1078-0432.CCR-24-2251.
Developing T-cell or vaccine therapies for pancreatic ductal adenocarcinoma (PDAC) has been challenging because of a lack of knowledge regarding immunodominant, cancer-specific antigens as PDAC are characterized by a scarcity of genomic mutation-associated neoepitopes, and effective approaches to discover them are limited.
An advanced mass spectrometry approach was employed to compare the immunopeptidome of PDAC tissues and matched normal tissues from the same patients.
This study identified HLA class I-binding variant peptides derived from canonical proteins, which had single amino-acid substitutions not attributed to genetic mutations or RNA editing. These amino-acid substitutions appeared to result from translational errors. The variant peptides were predominantly found in tumor tissues, with certain peptides common among multiple patients. Importantly, several of these variant peptides were more immunogenic than their wild-type counterparts.
The shared noncanonical neoepitopes identified in this study offer promising candidates for vaccine and T-cell therapy development, potentially providing new avenues for immunotherapy in PDAC. See related commentary by Yuan et al., p. 1821.
由于缺乏关于免疫显性、癌症特异性抗原的知识，开发用于胰腺导管腺癌（PDAC）的T细胞疗法或疫苗疗法一直具有挑战性，因为PDAC的特点是与基因组突变相关的新表位稀缺，且发现它们的有效方法有限。
采用先进的质谱方法比较同一患者的PDAC组织和匹配的正常组织的免疫肽组。
本研究鉴定了源自经典蛋白质的HLA I类结合变异肽，这些变异肽具有单个氨基酸取代，并非由基因突变或RNA编辑引起。这些氨基酸取代似乎是由翻译错误导致的。变异肽主要在肿瘤组织中发现，某些肽在多个患者中常见。重要的是，其中一些变异肽比其野生型对应物具有更强的免疫原性。
本研究中鉴定出的共享非经典新表位为疫苗和T细胞疗法的开发提供了有前景的候选物，可能为PDAC的免疫治疗提供新途径。见袁等人的相关评论，第1821页。
