Proteogenomics Platforms Establishing Personalized and Precision Neoantigen Therapeutics in Cancer

该项目旨在建立蛋白质组学平台，以发现癌症新药的新来源。其中一个研究模型将是T细胞淋巴瘤，它被认为是高度未得到满足的临床需求，也是发达国家高度重视的重点。比较癌症和正常样本的蛋白质基因组数据将产生丰富的突变抗原物来源，因为在这种淋巴瘤中已经发现了几种复发的遗传异常。该项目的第一阶段将使用当前的生物信息学软件来定义突变基因、突变的mRNA、RNA编辑事件、内含子翻译以及来自下一代DNA和RNA测序的染色体融合，以创建患者特有的突变蛋白质参考数据库；该参考数据库将成为使用质谱学来鉴定突变的MHC I类多肽的工具。下一步将包括开发细胞和组织模型，以测量人类癌症中主要的新抗原源。质谱学分析将测量新肽的所有来源都来自肿瘤细胞的程度。该项目的最后阶段将专注于开发疫苗模型。将上述平台应用于体外模型，为从患者中鉴定细胞毒性T细胞克隆和检测体外对淋巴瘤群体的Fort细胞杀伤作用提供了基础。关键问题是抑制RNA剪接或无义RNA衰退是否会增加MHC-I类突变抗原的呈递，但也会对从患者分离的现有T细胞致敏。

The project aims to establish proteogenomics platforms to discover new sources of cancer neoantigens.One of the study models will be T-cell lymphoma which is considered of high unmet clinical need andwhich is of high priority focus in developed countries. Comparing the proteogenomic data of cancerand normal samples will produce a rich source of mutant antigenic material, since several recurrentgenetic abnormalities have been discovered in such lymphomas.The first stage of the project will be to use current bioinformatics software to define mutated genes,mutant mRNA, RNA editing events, intron-translation, and chromosomal fusions from nextgeneration DNA and RNA sequencing to create a mutant protein reference database that is patientspecific; and this reference database would be a tool for identifying mutated MHC class I peptidesusing mass spectrometry. Next step will includedeveloping cell and tissue models to measure the dominating neoantigen source in human cancers. Mass spectrometric assays will measure the extent to which all sources of neopeptides are derived from tumour cells.Last stage of the project will focus on developing vaccine models. Applying the above platform to invitro models, gives the basis to identification of cytotoxic T-cell clones from patients and testing forT-cell killing of the lymphoma populations in vitro in combination with sets of mutant peptidevaccines.The key question would be whether inhibition of RNA splicing, or non-sense RNA decay increasesMHC Class I -mutated antigen presentation but also sensitize to existing T-cells isolated frompatients.