Abstract：
Emerging data have shown that previously defined noncoding genomes might encode peptides that bind human leukocyte antigen (HLA) as cryptic antigens to stimulate adaptive immunity1,2. However, the significance and mechanisms of action of cryptic antigens in anti-tumour immunity remain unclear. Here mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I-binding cryptic antigenic peptides that were noncanonically translated by a tumour-specific circular RNA (circRNA): circFAM53B. The cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen-specific cytotoxic T cells, which led to effective tumour control. Overall, our findings reveal that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.
摘要：
新出现的数据表明，先前定义的非编码基因组可能编码与人类白细胞抗原（HLA）结合的肽，作为隐蔽抗原，以刺激适应性免疫1,2。然而,隐匿性抗原在抗肿瘤免疫中的意义和作用机制尚不清楚。在此，HLAI类（HLA-I）肽组的质谱分析与人类乳腺癌样品的核糖体测序相结合，鉴定出HLA-I结合的隐性抗原肽，这些肽由肿瘤特异性环状RNA（circRNA）：circFAM53B进行非规范翻译。隐蔽肽以抗原特异性方式有效地引发幼稚CD4和CD8T细胞，并诱导抗肿瘤免疫。临床上,在乳腺癌和黑色素瘤患者中,circFAM53B及其编码肽的表达与抗原特异性CD8+T细胞的大量浸润以及更好的生存率相关.机械上,circFAM53B编码的肽对HLA-I和HLA-II分子均具有强结合亲和力。在体内,在患有乳腺癌肿瘤或黑色素瘤的小鼠中施用由肿瘤特异性circRNA或其编码的肽组成的疫苗，诱导肿瘤抗原特异性细胞毒性T细胞的浸润增强，这导致了有效的肿瘤控制。总的来说,我们的发现表明，circRNAs的非规范翻译可以驱动有效的抗肿瘤免疫，这表明利用肿瘤特异性circRNAs的疫苗接种可能作为针对恶性肿瘤的免疫治疗策略。
