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: 10404109
• 负责人: William Hildebrand
• 金额: $ 45.04万
• 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/10404109
• 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; canine model; 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; 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.

摘要 作为自然发生的，具有完整的免疫系统，宠物狗的自发性癌症具有 有可能有效地弥合临床前模型和人体临床试验之间的差距， 癌症免疫疗法然而，目前缺乏必要的资源， 犬类癌症这种缺陷在预测肿瘤特异性新抗原（TSNA）中明显可见， 癌症治疗和预防的目标。TSNA产生于细胞内突变肽， 癌症相关的体细胞改变，由细胞的组织相容性复合物I类（MHC-I） 分子。因此，MHC-I基因分型是TSNA预测的先决条件。然而，由于MHC-I等位基因很少， 迄今为止，对狗进行MHC-I基因分型是一个重大挑战。此外，由于非常有限的 MHC-I蛋白质晶体结构和实验肽结合数据，目前缺乏公共工具， 专门为狗预测TSNA，与人类开发的许多工具相反。 随着来自数百个品种的数千只狗的下一代测序（NGS）数据的公布， 现在是解决这些缺陷的时候了。我们建议通过以下方式将我们的专业知识、NGS数据分析与联合收割机相结合： Zhao（PI）实验室和Hildebrand（MPI）实验室的MHC-I表征，以开发软件工具和数据 大规模的MHC-I基因分型和系统的TSNA预测的狗的资源。我们还将 数千只狗的基因型MHC-I等位基因测序并预测数百只狗肿瘤的TSNA 表征了我们将使用我们提出的MHC-I基因型和TSNA发现工具，以协助NCI资助的 通过与Steven Dow博士合作进行的免疫治疗试验，以及犬癌疫苗接种研究 （VACCS）试验通过与道格拉斯塔姆博士合作。 通过建立目前严重缺乏的资源，我们的工作将大大加强 狗模型在转化研究中的适用性。