肿瘤细胞治疗研究
英文原题：Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues.
我们的新方法可指导用于治疗HBV相关HCC的双特异性抗体、TCR-T或CAR-T疗法的开发，并为疫苗研发提供信息。
感染细胞表面 HLA I 类分子呈递病毒来源肽，以及 CD8+ 细胞毒性 T 细胞对这些 HLA-肽复合物的识别和随后激活，构成了抗病毒免疫保护的重要机制。近年来 proteogenomics 的进展使研究人员发现了越来越多独特的 HLA 限制性病毒肽，从而迅速扩展了针对感染组织的免疫治疗靶点库（即双特异性抗体、工程化 T 细胞受体（TCR）、CAR-T 细胞）。然而，病毒株之间的基因组变异性，例如乙型肝炎病毒（HBV），再加上患者 HLA 等位基因的差异，使得针对这些靶点开发治疗药物变得困难。为应对这一挑战，我们开发了一种新的 proteogenomics 方法，用于生成患者特异性数据库，使基于从单个患者肝脏样本测序获得的病毒转录组来鉴定病毒肽成为可能。我们还利用患者样本的 DNA 测序来鉴定 HLA 基因型并协助靶点选择。我们检查了 48 名 HBV 感染患者（主要来自亚洲）的肝脏样本，以重建患者特异性 HBV 基因组，鉴定 HBV 整合所靶向的人类染色体区域，并使用我们的 HLA I 类（HLA-I）immunopeptidomics 发现平台获得 HBV 肽表位的全面视图。两个先前报道的 HLA 相关 HBV 来源肽，即来自大表面抗原的 HLA-A02 结合肽 FLLTRILTI（S 194-202）和来自衣壳蛋白的 HLA-A11 结合肽 STLPETTVVRR（C 141-151），被我们的发现平台验证，但两者的检出频率都非常低。此外，我们利用重肽类似物鉴定并验证了新的菌株特异性HBV-HLA相关肽，如GSLPQEHIVQK（P 606-616）及其变体。总体而言，我们的新方法可以指导用于治疗HBV相关HCC的双特异性抗体、TCR-T或CAR-T疗法的开发，并为疫苗开发提供信息。
The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8 + cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S 194-202 ) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C 141-151 ) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P 606-616 ) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.
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