Structural modeling of neoantigen presentation for rational design of heteroclitic neoepitope vaccines

项目摘要 胰腺导管腺癌(PDAC)对一线手术切除和 化疗。许多耐药癌症类型都受益于免疫疗法， 激活细胞毒性抗肿瘤T细胞，对抗癌细胞中表达的体细胞突变或新抗原。 发展新抗原靶向免疫疗法治疗pDAC的一个主要挑战是 已鉴定新抗原的数量和弱免疫原性。高效激活新抗原特异性T细胞 细胞依赖于人类白细胞抗原(人类白细胞抗原)上显示的8到11位新表位的识别 I类分子。这一认识是生物物理和立体化学联系的高潮 多肽、人类白细胞抗原和T细胞受体(TCR)分子。提高新表位的一种机制 免疫原性是通过修饰多肽氨基酸残基来增强人类白细胞抗原结合或TCR识别， 从而增强同源T细胞的激活，同时保持对亲本表位的反应性。这些修改后的 表位被称为异位表位。然而，异位表位的立体化学特征 增强人类白细胞抗原结合或TCR识别的研究还不够深入。此外，杂合表位已经被 在数量有限的人类白细胞抗原亚型的背景下进行探索，限制了它们的发展和应用 在所有病人之间。我们假设异源新表位疫苗的合理设计是通过结构 建模将提高T细胞对PDAC新抗原的反应。为了解决这一假设，我们将定义 共用和专有PDAC杂合新表位的结构结合和空间展示动力学 不同的HLA。在PDAC中表达的共同新抗原中，KRAS第12密码子的激活突变包括 出现在高达80%的PDAC肿瘤中。在具体目标1中，我们将审问结构力学和 18个具有全球代表性的人类白细胞抗原KRAS G12D/V/C表位的免疫原性分析 子类型。在具体目标2中，我们将开发一个计算管道来识别、排序和优化患者- 基于结构表位特征的特定异源新抗原候选疫苗。我们将使用人类白细胞抗原 结合测量和T细胞反应性分析来验证我们计算的免疫原性特征 模型化的异位表位。这些目标共同定义了免疫原性的结构特征。 不同HLA中的新抗原产生共享和私有PDAC的异源表位候选疫苗 抗原，并提高癌症疫苗对PDAC等难以治疗的癌症的治疗潜力。

Project Summary Pancreatic ductal adenocarcinoma cancer (PDAC) is highly resistant to frontline surgical resection and chemotherapy treatments. Many treatment-resistant cancer types have benefited from immunotherapies that activate cytotoxic anti-tumor T cells against the somatic mutations, or neoantigens, expressed in cancer cells. One major challenge to the development of neoantigen-targeted immunotherapy for PDAC has been the low number and weakly immunogenic profile of identified neoantigens. Efficient activation of neoantigen-specific T cells is dependent on the recognition of 8- to 11-mer neoepitopes displayed on human leukocyte antigen (HLA) class I molecules. This recognition is the culmination of the biophysical and stereochemical contacts between the peptide, HLA, and T cell receptor (TCR) molecules. One mechanism to improve neoepitope immunogenicity is by modifying the peptide amino acid residues to enhance HLA binding or TCR recognition, thereby enhancing cognate T cell activation, while conserving reactivity to the parental epitope. These modified epitopes are termed heteroclitic epitopes. However, the stereochemical features of heteroclitic epitopes that enhance HLA binding or TCR recognition are understudied. Additionally, heteroclitic epitopes have been explored in the context of a limited number of HLA subtypes, restricting their development and application across patients. We hypothesize that rational design of heteroclitic neoepitope vaccines through structural modelling will improve T cell responses against PDAC neoantigens. To address this hypothesis, we will define the structural binding and spatial display dynamics of both shared and private PDAC heteroclitic neoepitopes in diverse HLAs. Among shared neoantigens expressed in PDAC, activating mutations in KRAS at codon 12 are present in up to 80% of PDAC tumors. In Specific Aim 1, we will interrogate the structural mechanics and immunogenic profile of heteroclitic KRAS G12D/V/C epitopes in a panel of 18, globally representative HLA subtypes. In Specific Aim 2, we will develop a computational pipeline to identify, prioritize and optimize patient- specific heteroclitic neoantigen vaccine candidates based on structural epitope features. We will use HLA binding measurements and T cell reactivity assays to validate immunogenic features of our computationally modelled heteroclitic epitopes. Together, these aims will define the structural features of immunogenic neoantigens in diverse HLAs, generate heteroclitic epitope vaccine candidates for shared and private PDAC antigens, and improve the therapeutic potential of cancer vaccines for hard-to-treat cancers such as PDAC.