Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Cancer Immunol Res. 2019 May;7(5):797-804. doi: 10.1158/2326-6066.CIR-18-0137. Epub 2019 Mar 19.
MHC-bound peptides from aberrant proteins may be a specific immunotherapeutic target on cancer cells. Because of difficulties in identifying such antigens, viral or model antigens have so far been used to study their biological relevance. We here identify a naturally existing human T-cell epitope derived from a truncated protein. The antigenic peptide is derived from the gene only through an alternative transcript containing a premature termination codon that may target the transcript for nonsense-mediated decay (NMD). This antigen is recognized by HLA-A*02:01-restricted CD8 T cells derived from an allotransplanted leukemia patient. Functional analyses showed that these T cells failed to recognize several HLA-matched primary leukemic cells that expressed the alternative transcript. Conventional antigen processing and presentation were not affected, suggesting that leukemic cells modify the generation of antigens processed from aberrant proteins. This natural TTK epitope provides insights in the source of transcripts producing antigenic epitopes in healthy and leukemic cells. Our data underscore potential pitfalls of targeting NMD-derived or other unconventionally generated epitopes as immunotherapeutic approach.
MHC 结合的异常蛋白肽可能是癌细胞的特定免疫治疗靶点。由于识别此类抗原存在困难，到目前为止，病毒或模型抗原一直被用于研究其生物学相关性。在这里，我们鉴定了一个源自截断蛋白的天然存在的人类 T 细胞表位。该抗原肽仅通过含有提前终止密码子的替代转录本从基因 衍生而来，该转录本可能靶向无意义介导的衰变 (NMD) 的转录本。这种抗原被来自同种异体移植白血病患者的 HLA-A*02:01 限制性 CD8 T 细胞识别。功能分析表明，这些 T 细胞无法识别表达替代转录本的几种 HLA 匹配的原发性白血病细胞。常规的抗原加工和呈递不受影响，这表明白血病细胞修饰了从异常蛋白加工产生的抗原的生成。这个天然的 TTK 表位为健康和白血病细胞中产生抗原表位的转录本的来源提供了深入了解。我们的数据强调了作为免疫治疗方法靶向 NMD 衍生或其他非传统产生的表位的潜在陷阱。
