RNA Polymerase III specific CD8+ T cells: a mechanistic insight into cancer-induced autoimmunity in scleroderma

RNA聚合酶III特异性CD8 T细胞：硬皮病中癌症诱导的自身免疫的机制洞察

基本信息

批准号：
10301593
负责人：
Eleni Tiniakou
金额：
$ 15.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301593
关键词：
Address Affect Antibodies Antigens Antitumor Response Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Award Bioinformatics Biological Assay Blood Cells Blood Vessels CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cells Complex Cross Presentation Cytotoxic T-Lymphocytes Data Dendritic Cells Development Diagnostic Disease Epitopes Etiology Fibrosis Flow Cytometry Foundations Frequencies Future Genes Goals Grant Granzyme Immune response Immune system Immunoglobulins Immunologic Surveillance Immunologics Immunology Immunotherapy Lead Link Loss of Heterozygosity Lung MHC Class I Genes Malignant Neoplasms Measures Mediating Mentors Monitor Morbidity - disease rate Mutate Mutation Names Pathogenesis Patients Peptides Phenotype Play Population Property Proteins Publications RNA Polymerase III Recording of previous events Research Personnel Resources Rheumatism Rheumatology Role Sampling Scleroderma Shapes Site Skin Skin Tissue Somatic Mutation Specificity Systemic Scleroderma T cell receptor repertoire sequencing T cell response T-Lymphocyte T-Lymphocyte Epitopes Technology Therapeutic Time Tissues Translational Research Tumor Immunity Tumor Tissue Vascular Diseases Work anti-cancer anti-tumor immune response antigen processing antigen-specific T cells autoreactivity cancer cell cancer risk cancer site career career development cytotoxic cytotoxic CD8 T cells design experience insight mortality neoplastic cell nonsynonymous mutation novel peptide I peripheral blood pressure skills skin disorder skin fibrosis skin lesion therapeutic target tool tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Increasing evidence suggests an immunologic link between cancer and autoimmunity. The immune system is able to reject cancer through recognition of altered self-antigens; however, recognition of self-antigens in healthy tissues could lead to autoimmunity. Scleroderma, or systemic sclerosis (SSc), offers a unique opportunity to study this relationship since patients with autoantibodies to RNA polymerase III (RPC1) have an increased risk of cancer coincident with SSc onset. Genetic alterations (somatic mutations or loss of heterozygosity, LOH) within the RNA polymerase III locus (protein name RPC1) were identified in cancers from anti-RPC1+ SSc patients and distinct populations of CD4+ T cells were detected that recognized normal and mutated versions of RPC1. Together, these observations suggest that antitumor immunity initiated against the mutated RPC1 protein could cross-react with the wild-type protein and lead to SSc. While CD4+ T cells are critical in orchestrating anti- tumor immune responses, CD8+ T cells are critical for eliminating tumor cells. Moreover, the observed LOH suggests that tumor immunoediting driven by RPC1-specific CD8+ T cells occurred in these patients, and at the same time, there is increasing evidence implicating CD8+ T cells in SSc pathogenesis. An important outstanding question remains: whether RPC1-specific cytotoxic T cells can be identified in patients with SSc and cancer. This proposal seeks to investigate RPC1-specific CD8+ T cells in the peripheral blood and target tissues of patients with SSc and cancer. Aim 1 will examine RPC1-specific CD8+ T cells that are directly involved in both the antitumor response at the site of the cancer as well as in the autoimmune damage of affected skin tissue from SSc patients. In Aim 2, the frequency, phenotype, and effector molecules of RPC1-specific CD8+T-cells will be studied and correlated with cancer status. Finally, Aim 3 will examine the effect of anti-RPC1 autoantibodies on cross-presentation, and potential differences between anti-RPC1+ SSc patients with and without history of cancer. The results of this study will lay the foundation for future studies exploring whether CD8+ T cell responses to RPC1 could be used as targeted monitoring tools and the RPC1 CD8+ T cell epitopes as antigen-specific immunotherapies for SSc, as well as inform the study of other cancer-associated rheumatic diseases. This K08 proposal is designed to promote the career development of the candidate to an independent investigator. To successfully carry out this proposal, she has assembled an outstanding team of mentors, each of whom brings distinct expertise to her project and her scientific development. Moreover, this proposal takes advantage of the rich resources of the Johns Hopkins Scleroderma Center. Building on the candidate’s previous experience studying antigen-specific T cell immunology and antigen processing, this K08 award will enable her to gain additional skills in bioinformatics important for the conduct of translational immunology, develop expertise in the specific niche of autoreactive CD8+ T cells as it pertains to autoimmunity and cancer, and acquire the data and publications necessary to support a strong R01 application.

项目概要/摘要越来越多的证据表明癌症和自身免疫之间存在免疫联系。能够通过识别改变的自身抗原来拒绝癌症；然而，识别健康的自身抗原；组织可能导致自身免疫性硬皮病或系统性硬化症（SSc），这提供了独特的机会。研究这种关系，因为携带 RNA 聚合酶 III (RPC1) 自身抗体的患者风险增加癌症与 SSc 发病同时发生基因改变（体细胞突变或杂合性缺失，LOH）。在来自抗 RPC1+ SSc 的癌症中鉴定出 RNA 聚合酶 III 基因座（蛋白质名称 RPC1）内的检测到与 CD4+ T 细胞不同的患者和群体可以识别正常和突变版本的 CD4+ T 细胞总之，这些观察结果表明针对突变的 RPC1 蛋白启动了抗肿瘤免疫。可能与野生型蛋白发生交叉反应并导致 SSc，而 CD4+ T 细胞在协调抗-SSc 方面至关重要。免疫肿瘤反应中，CD8+ T 细胞对于消除肿瘤细胞至关重要。此外，观察到的 LOH。表明由 RPC1 特异性 CD8+ T 细胞驱动的肿瘤免疫编辑发生在这些患者中，并且在同时，越来越多的证据表明 CD8+ T 细胞是 SSc 发病机制中的一个重要的突出因素。问题仍然存在：是否可以在 SSc 和癌症患者中鉴定出 RPC1 特异性细胞毒性 T 细胞。该提案旨在研究外周血和靶组织中的 RPC1 特异性 CD8+ T 细胞目标 1 将检查与 SSc 和癌症直接相关的 RPC1 特异性 CD8+ T 细胞。癌症部位的抗肿瘤反应以及受影响皮肤组织的自身免疫损伤在目标 2 中，来自 SSc 患者的 RPC1 特异性 CD8+T 细胞的频率、表型和效应分子。最后，目标 3 将检查抗 RPC1 的效果。自身抗体交叉呈递，以及抗 RPC1+ SSc 患者和患者之间的潜在差异这项研究的结果将为未来探索是否有癌症病史的研究奠定基础。 CD8+ T 细胞对 RPC1 的反应可用作靶向监测工具，RPC1 CD8+ T 细胞表位作为 SSc 的抗原特异性免疫疗法，并为其他癌症相关风湿病的研究提供信息该K08提案旨在促进候选人的职业发展为独立。为了成功地实施这一提议，她组建了一支优秀的导师团队，每一位导师都非常出色。此外，该提案还为她的项目和科学发展带来了独特的专业知识。充分利用约翰·霍普金斯大学硬皮病中心的丰富资源。研究抗原特异性 T 细胞免疫学和抗原加工的经验，这个 K08 奖将使她能够获得对进行转化免疫学很重要的生物信息学额外技能，发展专业知识在与自身免疫和癌症有关的自身反应性 CD8+ T 细胞的特定生态位中，并获取数据以及支持强大的 R01 申请所需的出版物。