Canine MHC-I genotyping and tumor specific neoantigen determination

犬 MHC-I 基因分型和肿瘤特异性新抗原测定

• 批准号: 10220542
• 负责人: William Hildebrand
• 金额: $ 49.2万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-11 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220542
• 关键词: Address; Advanced Malignant Neoplasm; Algorithms; Alleles; Base Pairing; Behavior Therapy; Binding; Canis familiaris; Cell Culture Techniques; Cell Line; Cells; Clinical; Clinical Data; Clinical Trials; Collaborations; Crystallization; Data; Data Analyses; Data Commons; Databases; Development; Etiology; Funding; Genome; Genotype; Heterogeneity; Human; Immune system; Institutes; Major Histocompatibility Complex; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Modeling; Molecular; National Cancer Institute; Neural Network Simulation; Oncology; Outcome; Peptides; Population; Pre-Clinical Model; Proteins; Publishing; Quality Control; Research; Resources; Rodent Model; Sampling; Sequence Read Archive; Software Tools; Structure; Time; Training; Translating; Translational Research; Treatment outcome; Vaccination; Validation; Work; artificial neural network; cancer immunotherapy; cancer prevention; cancer therapy; data resource; exome sequencing; experience; genome sequencing; human genomics; immunogenicity; immunotherapy trials; mutant; neoantigens; next generation sequencing; pre-clinical; prevent; software development; success; tool; transcriptome; transcriptome sequencing; translational model; tumor; whole genome

Abstract Being naturally occurring and with an intact immune system, spontaneous cancers in pet dogs have the potential to effectively bridge a current gap between preclinical models and human clinical trials, advancing cancer immunotherapy. However, a current lack of essential resources creates roadblocks to the effective use of canine cancers. The deficiency is clearly seen in predicting tumor-specific neoantigen (TSNA), attractive targets in cancer treatment and prevention. TSNAs arise when intracellular mutant peptides, created by cancer-associated somatic alterations, are presented by the cell’s histocompatibility complex class I (MHC-I) molecules. Hence, MHC-I genotyping is a prerequisite for TSNA prediction. However, with few MHC-I alleles known to date, MHC-I genotyping for the dog is a significant challenge. Moreover, because of the very limited MHC-I protein crystal structures and experimental peptide binding data, there currently lack public tools to predict TSNAs specifically for the dog, in contrast to the human with many tools developed. With the next generation sequencing (NGS) data published for thousands of dogs from hundreds of breeds, now is the time to address these deficiencies. We propose to combine our expertise, NGS data analysis by the Zhao (PI) lab and MHC-I characterization by the Hildebrand (MPI) lab, to develop software tools and data resources for large scale MHC-I genotyping and systematic TSNA prediction for the dog. We will also genotype MHC-I alleles of thousands of dogs sequenced and predict TSNAs for hundreds of canine tumors characterized. We will use our proposed MHC-I genotype and TSNA discovery tools to assist a NCI-funded immunotherapy trial via collaboration with Dr. Steven Dow, and the Vaccination Against Canine Cancer Study (VACCS) trial via collaboration with Dr. Douglas Thamm. By establishing resources that are critically missing at present, our work will significantly enhance the applicability of the dog model for translational research.

抽象的 天然发生并且有完整的免疫系统，宠物狗的赞助商具有 有效弥合临床前模型和人类临床试验之间的当前差距的潜力 癌症免疫疗法。但是，目前缺乏基本资源为有效用途创造了障碍 犬癌。在预测肿瘤特异性新抗原（TSNA）时清楚地看到了这种缺陷，吸引人 癌症治疗和预防的目标。当细胞内突变体辣椒形成时，TSNA出现 该细胞的组织相容性复合物I类（MHC-I）提出了与癌症相关的体细胞改变 分子。因此，MHC-I基因分型是TSNA预测的先决条件。但是，很少有MHC-I等位基因 迄今为止，狗的MHC-I基因分型是一个重大挑战。而且，由于非常有限 MHC-I蛋白质晶体结构和实验性肽结合数据，目前缺乏公共工具 与人类使用许多工具相比，专门为狗预测TSNA。 随着下一代测序（NGS）的数据发布，该数据针对数百种品种的数千只狗， 现在是解决这些缺陷的时候了。我们建议通过 Zhao（PI）实验室和MHC-I通过Hildebrand（MPI）实验室表征，以开发软件工具和数据 大规模MHC-I基因分型和系统的TSNA预测资源。我们也会 成千上万的狗的基因型MHC-I等位基因测序并预测数百种犬肿瘤的TSNA 特征。我们将使用建议的MHC-I基因型和TSNA发现工具来帮助NCI资助 免疫疗法试验通过与Steven Dow博士合作以及针对犬类癌症的疫苗接种 （VACC）通过与Douglas Thamm博士合作进行试验。 通过建立目前严重缺乏的资源，我们的工作将大大增强 狗模型在翻译研究中的适用性。