Mapping tumor specific immunopeptidome for antibody-based targeted therapy

绘制肿瘤特异性免疫肽组用于基于抗体的靶向治疗

基本信息

批准号：
10604941
负责人：
Zi Yao
金额：
$ 6.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604941
关键词：
Affinity Alleles Alternative Splicing Antibodies Antigen Presentation Antitumor Response Autoimmune BRAF gene Benchmarking Biological Biological Assay Biological Products Cancer cell line Cancerous Cell Line Cell model Cell surface Cells Complement Complex Cultured Cells Cytotoxic T-Lymphocytes Data Databases Development Disease Disease model Engineering Epidermal Growth Factor Receptor Epitopes Foundations Future Generations Genetic Transcription Goals HLA Antigens Immune Immune response Immune system Immunologic Surveillance Immunotherapy In Vitro Individual Intervention Investigation KRAS2 gene MEKs Malignant Neoplasms Maps Mass Spectrum Analysis Membrane Proteins Modality Molecular Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogene Activation Oncogenes Oncogenic Oncoproteins Parents Patients Peptides Phage Display Phenotype Protein Databases Proteins Proteolysis Proteome RNA Splicing Reagent Recombinant Antibody Recovery Research Safety Sampling Shapes Signal Pathway Signal Transduction Specificity Surveys SwissProt T-Cell Activation T-Lymphocyte Techniques Technology Testing Therapeutic Transcript Tumor Immunity Tumor Specific Peptide Work anti-tumor immune response antibody engineering arm cancer cell cancer type cell transformation chimeric antigen receptor design driver mutation humanized mouse in vivo inhibitor insight interest mouse model neoantigens novel overexpression patient population prostate cancer cell line recruit targeted treatment therapeutic target tool tumor tumor eradication tumorigenesis vector control

项目摘要

Project Summary Antibody-based immunotherapies have become an established paradigm for treating cancers. Only a small portion of patients have benefited from these agents, though, and many are only effective for treating a small set of tumors. This is due, in part, to a lack of validated cell surface targets. Only a dozen of surface proteins has been approved for antibody intervention, and most are not truly exclusive to malignant cells. There has been growing interesting in searching the cellular immunopeptidome for tumor-exclusive targets. The immunopeptidome is a pool of peptides generated from proteolysis of intracellular proteins and displayed on the cell surface as a complex with the human leukocyte antigens (HLA). It is thought that this peptide repertoire reflects the status of the intracellular proteome and can be modulated by driver oncogenes. Epitopes harboring driver mutations, or neo-antigens, have been detected as peptide-HLA complexes (pHLAs) from tumor samples. However, the mechanism of how oncogene signaling shape the immunopeptidome remains uncharacterized. The goals of this proposal are to develop technologies to map changes in the immunopeptidome unique to specific ongene, and tools to mount an immune response against them. These findings will ultimately aid in developing antibody-based biologics with better safety profile and more applicable to diverse types of cancers. Here, we hypothesized that proliferative oncogenes globally alter the immunopeptidome via transcriptional remodeling and alternative splicing, and induce unique pHLAs beyond mutated fragments of parent oncoproteins. To test this hypothesis, we will first develop a new mass spectrometry technique to map diseased immunopeptidome in an allele-specific manner. Next, we will combine this technique with a reductionist cell model approach to study the immunopeptidome of isogenic cell lines overexpressing specific oncogene. The immunopeptidomics data will be complemented by protein databases and transcript analyses to reveal key contributors of oncogene-specific pHLAs. Collectively, the proposed work will provide insight to how a single genetic alteration can impact mechanisms of antigen presentation and produce neo-antigens on the cell surface. To build on these discoveries, we will also engineer antibodies to recognize pHLAs of interest with high affinity and peptide specificity. These reagents will be further elaborated into chimeric antigen receptors to arm cytotoxic T cells and mount antitumor response against cells displaying oncogene-specific pHLAs. These reagents will be tested in cultured cells, and humanized mice models. In the long term, the basic biological insights and antibody tools generated from the proposed studies will bolster ongoing efforts to understanding the cancerous immunopeptidome and lay the foundation for future therapeutics targeting neo-antigens.

项目概要基于抗体的免疫疗法已成为治疗癌症的既定范例。只有一个小不过，部分患者已从这些药物中受益，而且许多仅对一小部分患者有效肿瘤。这部分是由于缺乏经过验证的细胞表面靶点。只有十几种表面蛋白已被批准用于抗体干预，并且大多数并不是真正专属于恶性细胞。已经有人们对在细胞免疫肽组中寻找肿瘤特异性靶点越来越感兴趣。这免疫肽组是由细胞内蛋白质水解产生的肽池，并显示在细胞表面与人类白细胞抗原 (HLA) 形成复合物。据认为，该肽库反映了细胞内蛋白质组的状态，并且可以通过驱动癌基因进行调节。表位隐藏驱动突变或新抗原已从肿瘤样本中以肽-HLA 复合物 (pHLA) 的形式被检测到。然而，癌基因信号传导如何塑造免疫肽组的机制仍不清楚。该提案的目标是开发技术来绘制免疫肽组特有的变化图谱特定的原基因，以及针对它们发起免疫反应的工具。这些发现最终将有助于开发基于抗体的生物制剂，具有更好的安全性，更适用于多种类型的癌症。在这里，我们假设增殖癌基因通过转录整体改变免疫肽组重塑和选择性剪接，并诱导超出亲本突变片段的独特 pHLA 癌蛋白。为了检验这一假设，我们将首先开发一种新的质谱技术来绘制患病的图谱以等位基因特异性方式的免疫肽组。接下来，我们将把这项技术与还原细胞结合起来研究过度表达特定癌基因的同基因细胞系的免疫肽组的模型方法。这免疫肽组学数据将得到蛋白质数据库和转录本分析的补充，以揭示关键癌基因特异性 pHLA 的贡献者。总的来说，拟议的工作将深入了解单个遗传改变可以影响抗原呈递机制并在细胞表面产生新抗原。为了以这些发现为基础，我们还将设计抗体以高亲和力识别感兴趣的 pHLA 和肽特异性。这些试剂将被进一步精心制作成嵌合抗原受体，以武装细胞毒性 T 细胞会对展示癌基因特异性 pHLA 的细胞产生抗肿瘤反应。这些试剂将在培养细胞和人源化小鼠模型中进行了测试。从长远来看，基本的生物学见解和抗体拟议研究产生的工具将支持正在进行的了解癌症的努力免疫肽组，为未来针对新抗原的治疗奠定基础。