"Post-translational modification of non-histone proteins as a mechanism of pMHC-I neo-ligand generation"

“非组蛋白蛋白的翻译后修饰作为 pMHC-I 新配体生成的机制”

基本信息

批准号：
10583511
负责人：
ROBERT K BRIGHT
金额：
$ 7.65万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-03 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10583511
关键词：
Acetylation Address Advanced Malignant Neoplasm Affect Affinity Amino Acids Antibody Response Antigens Autoantigens Autoimmune Avidity Behavior CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Cell model Cells Data Deacetylase Deacetylation Development Discrimination Epitopes Generations Goals Immune Immune Targeting Immunity Immunotherapy In Vitro Incubated Investigation Knowledge Letters Life Ligands Lysine Malignant - descriptor Masks Mass Spectrum Analysis Metastatic Neoplasm to the Lung Mission Modeling Modification Monitor Mus Neoplasm Metastasis Non-Malignant Normal Cell Oncogenic Organism Peptide/MHC Complex Peptides Post-Translational Protein Processing Proteins Public Health Regulation Regulatory T-Lymphocyte Reporting Research T-Lymphocyte TPD52 gene Testing Thymus Gland Tissues Toxic effect Tumor Immunity United States National Institutes of Health Vaccinated Vaccination Vaccine Antigen Vaccines Work blind burden of illness cancer cell cancer immunotherapy cancer prevention cancer vaccination clinical application immune checkpoint blockade improved in vivo in vivo Model inhibitor neoantigens non-histone protein novel novel vaccines overexpression pre-clinical prevent tumor tumor growth tumor microenvironment tumorigenesis vaccine failure

项目摘要

Project Summary Abstract The advancement of cancer vaccines requires a deeper understanding of T cell recognition of malignant vs non-malignant cells. Though the T cell immune repertoire is developmentally regulated by negative and positive selection, T cells capable of recognizing self-proteins do exist and are critical effectors for many cancer immunotherapies. What remains unclear is how CD8+ CTLs elicited against tumor-self proteins are capable of recognizing malignant cells yet remain blind to healthy cells that also express the self-protein. Lack of clarity on this issue may inhibit the advancement of cancer vaccines that target non-mutated, oncogenic, tumor-self proteins. Our long-term goal is a deeper understanding of how tumor-self antigen vaccine elicited CTLs recognize cancer cells but do not recognize normal cells that also express the antigen. Our immediate objective, defining the first critical step toward our long-term goal, is to determine if a difference in malignant and non-malignant cell post-translation modification of a relevant, model tumor-self antigen generates pMHC-I- neo-ligand(s) recognized on cancer cells by vaccine elicited CTLs. We hypothesize that post-translational deacetylation of lysine residues within a relevant, model tumor-self protein naturally differs between malignant and non-malignant cells resulting in the generation of pMHC-I-neo-epitopes on malignant cells. Guided by supportive preliminary data, our hypothesis will be tested with two specific aims: 1) Determine if tumor-self antigen-lysine deacetylation in malignant cells enables recognition by tumor-self antigen vaccine elicited CTLs. Using mass spectroscopy, we expect to define differential acetylation of lysine residues in the relevant, model, oncogenic tumor-self protein D52 expressed in malignant and non-malignant cells. We expect to demonstrate that D52 lysine acetylation effects D52 vaccine elicited CTL recognition of malignant cells resulting in differential CTL discrimination of malignant and non-malignant cells. Using a specific panel of peptides derived from D52, we anticipate that we will define D52 vaccine elicited CTL pMHC-I-neo-epitopes. 2) Determine if tumor-self antigen-lysine deacetylation in malignant cells impacts vaccine induced protective tumor immunity. Using malignant cells incubated with deacetylase inhibitor prior to inoculation into D52 vaccinated mice with monitoring of tumor growth overtime and endpoint assessment of lung metastases, we expect to demonstrate that inhibition of natural deacetylation of D52 in malignant cells impacts pMHC-I- epitopes that are recognized by CTLs possibly resulting in failure of the vaccine to protect against tumor growth and metastases. Impact: The results of this proof of concept project are expected to positively impact the development of more effective next-generation vaccines that target oncogenic tumor-self proteins for the safe treatment or prevention of cancer. Equally important is a deeper understanding of immunotherapy elicited CTLs and malignant, non-malignant cell discrimination that may impact auto-immune-related toxicities as has been reported for immune checkpoint blockade, and may be associated with next-generation vaccines.

项目概要摘要癌症疫苗的进步需要更深入地了解 T 细胞识别恶性和非恶性细胞。尽管 T 细胞免疫库在发育过程中受到负和正选择，能够识别自身蛋白的 T 细胞确实存在，并且是许多细胞的关键效应器。癌症免疫疗法。目前尚不清楚的是 CD8+ CTL 是如何引发针对肿瘤自身蛋白的能够识别恶性细胞，但对也表达自身蛋白的健康细胞仍然视而不见。缺少这个问题的明确性可能会阻碍针对非突变、致癌、肿瘤自身蛋白。我们的长期目标是更深入地了解肿瘤自身抗原疫苗如何引发 CTL 识别癌细胞，但不识别也表达抗原的正常细胞。我们的即时目标，确定实现我们长期目标的第一个关键步骤，是确定恶性程度是否存在差异相关模型肿瘤自身抗原的非恶性细胞翻译后修饰生成 pMHC-I- 疫苗在癌细胞上识别的新配体引发了 CTL。我们假设翻译后相关模型肿瘤自身蛋白中赖氨酸残基的脱乙酰化在恶性细胞之间自然不同和非恶性细胞，导致恶性细胞上产生pMHC-I-新表位。指导者根据初步数据的支持，我们的假设将通过两个具体目标进行检验：1）确定肿瘤自身是否恶性细胞中的抗原赖氨酸脱乙酰作用使得肿瘤自身抗原疫苗能够识别引发 CTL。使用质谱法，我们期望定义赖氨酸残基的差异乙酰化相关模型致癌肿瘤自身蛋白 D52 在恶性和非恶性细胞中表达。我们期望证明 D52 赖氨酸乙酰化作用 D52 疫苗引发恶性细胞的 CTL 识别导致恶性和非恶性细胞的 CTL 区别。使用特定面板由于 D52 衍生的肽，我们预计我们将定义 D52 疫苗引发的 CTL pMHC-I-neo 表位。 2）确定恶性细胞中肿瘤自身抗原赖氨酸脱乙酰化是否影响疫苗诱导保护性肿瘤免疫。在接种前使用与脱乙酰酶抑制剂一起孵育的恶性细胞 D52 疫苗接种小鼠随时间监测肿瘤生长和肺转移终点评估，我们期望证明抑制恶性细胞中 D52 的自然脱乙酰化会影响 pMHC-I- 被 CTL 识别的表位可能导致疫苗无法预防肿瘤生长和转移。影响：该概念验证项目的结果预计将产生积极影响开发针对致癌肿瘤自身蛋白的更有效的下一代疫苗安全治疗或预防癌症。同样重要的是对免疫疗法有更深入的了解 CTL 和恶性、非恶性细胞区分可能会影响自身免疫相关毒性，据报道，它与免疫检查点阻断有关，并且可能与下一代疫苗有关。