Mechanisms of Thyroid Autoimmunity in Checkpoint Immunotherapy

检查点免疫治疗中甲状腺自身免疫的机制

• 批准号: 10454346
• 负责人: Melissa G Lechner
• 金额: $ 17.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454346
• 关键词: Acceleration; Advanced Malignant Neoplasm; Antibodies; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Award; B-Lymphocytes; BLR1 gene; Bioinformatics; Bladder; Breast; CD8B1 gene; CTLA4 gene; California; Cancer Patient; Cells; Cessation of life; Clinical; Colon; Data; Development; Development Plans; Doctor of Medicine; Doctor of Philosophy; Endocrine; Endocrinology; Evaluation; Faculty; Fine needle aspiration biopsy; Fine-needle biopsy; Functional disorder; Gland; Hashimoto Disease; Head and neck structure; Hospitalization; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunotherapy; Infiltration; Interruption; Iodide Peroxidase; Kidney; Lead; Liver; Los Angeles; Lung; Lymphocyte; Malignant Neoplasms; Mediating; Medicine; Melissa; Mentors; Modeling; Mus; Organ; Pathogenicity; Pathway interactions; Patients; Peripheral; Phage Display; Physicians; Population; Postdoctoral Fellow; Production; Proteins; Proteomics; Reporting; Research; Research Personnel; Role; Sampling; Scientist; Students; T cell response; T-Lymphocyte; Techniques; Testing; Thyroglobulin; Thyroid Diseases; Thyroid Gland; Thyroiditis; Tissues; Toxic effect; Training; Tumor-infiltrating immune cells; Universities; Work; anti-cancer; antitumor effect; autoimmune pathogenesis; autoimmune thyroid disease; autoimmune toxicity; autoimmunity checkpoint; cancer immunotherapy; cancer therapy; career development; checkpoint inhibition; checkpoint therapy; clinical care; cytokine; design; experience; genetic regulatory protein; immune activation; immune-related adverse events; improved; improved outcome; inhibitor; mouse model; neoplastic cell; next generation; novel; prevent; professor; programmed cell death protein 1; response; side effect; skills; transcriptomics

PROJECT SUMMARY Proposed is a five-year research career development plan focused on evaluating the mechanisms of thyroid autoimmunity during cancer immunotherapy. The candidate, Dr. Melissa G. Lechner, M.D., Ph.D., is an Assistant Professor of Medicine in Endocrinology at the University of California, Los Angeles (UCLA). This proposal builds upon her strong background and provides new training in mouse models of autoimmunity, advanced transcriptomic and proteomic techniques, and bioinformatics. During the award term, Dr. Lechner will be mentored by Dr. Maureen Su, M.D., a leader in the field of autoimmune disease and experienced physician scientist with a track record of mentoring more than 30 students, post-doctoral fellows, and junior faculty. She will have additional support from co-mentor Dr. Greg Brent, M.D., a renowned thyroid researcher, and a strong team of advisors with technical and content expertise. Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer treatment, but their use is limited by the development of unwanted autoimmune side effects seen in up to 60% of patients. These immune-related adverse events (IrAE) interrupt cancer treatment and lead to organ dysfunction, hospitalization, and even death. The cause of IrAEs remains unknown, however, recent data suggest that toxicity can be uncoupled from anti- tumor effects. Thyroiditis, a common IrAE, is ideal for studying mechanisms of IrAE development because of the ability to directly sample immune infiltrates in the thyroid by fine needle biopsy and to compare with Hashimoto’s thyroiditis (HT), a well-described spontaneous thyroid autoimmune disease. Interestingly, ICI-thyroiditis has both similar and distinct features from HT. Dr. Lechner developed a mouse model that recapitulates human IrAEs from checkpoint immunotherapy, including multi-organ immune infiltrates and autoantibodies. Using this model, she has identified a role for RORg+ Th17 and Tc17 cells and T peripheral helper (TPH, CXCR5-ICOS+PD1+) cells in IrAEs. These cell populations have previously been associated with spontaneous autoimmune diseases, including HT, but not yet IrAE. Additionally, studies in patients with checkpoint-inhibitor thyroiditis showed intrathyroidal T cell accumulation and increased RORg+ T cells. Therefore, in Specific Aim 1, Dr. Lechner will determine the role of RORg+ Th17 and Tc17 and TPH cells in IrAE development using a mouse model and analysis of thyroid-infiltrating cells patients with ICI-thyroiditis vs. HT. The absence of autoantibodies to known thyroid antigens (e.g. thyroid peroxidase thyroglobulin) in many ICI-thyroiditis patients also suggests immune attack against yet unidentified targets. Thus, in Specific Aim 2, Dr. Lechner will identify the antigen targets in ICI thyroiditis, evaluate immune responses to these antigens, and compare them known antigens in HT. With this work, Dr. Lechner aims to advance our understanding of mechanisms underlying thyroid autoimmune disease and checkpoint immunotherapy toxicities, and obtain the skills needed to become an independent investigator.

项目概要 提出了一个五年研究职业发展计划，重点评估 癌症免疫治疗期间的甲状腺自身免疫 候选人 Melissa G. Lechner 博士是一位医学博士、博士。 加州大学洛杉矶分校 (UCLA) 内分泌学医学助理教授。 该提案建立在她强大的背景之上，并提供了小鼠自身免疫模型的新培训， 先进的转录组学和蛋白质组学技术以及生物信息学。 受到自身免疫性疾病领域的领军人物、经验丰富的医师 Maureen Su 博士的指导 她是一位科学家，曾指导过 30 多名学生、博士后研究员和初级教师。 将获得共同导师 Greg Brent 博士（医学博士、著名甲状腺研究人员）和强大的支持 具有技术和内容专业知识的顾问团队。 免疫检查点抑制剂 (ICI) 疗法彻底改变了癌症治疗，但其用途有限 高达 60% 的患者会出现不良的自身免疫副作用。 不良事件（IrAE）中断癌症治疗并导致器官功能障碍、住院治疗，甚至死亡。 IrAE 的原因仍不清楚，然而，最近的数据表明，毒性可以与抗 甲状腺炎是一种常见的 IrAE，由于具有以下特点，因此非常适合研究 IrAE 的发生机制。 能够通过细针活检直接对甲状腺中的免疫浸润进行取样，并与桥本进行比较 甲状腺炎（HT），一种众所周知的自发性甲状腺自身免疫性疾病。 Lechner 博士开发了一种重现人类 IrAE 的小鼠模型。 通过检查点免疫疗法，包括多器官免疫浸润和自身抗体，使用该模型。 她确定了 RORg+ Th17 和 Tc17 细胞以及 T 外周辅助细胞（TPH、CXCR5-ICOS+PD1+）细胞的作用 在 IrAE 中，这些细胞群以前与自发性自身免疫性疾病有关， 此外，针对检查点抑制剂甲状腺炎患者的研究表明，包括 HT，但尚未包括 IrAE。 甲状腺内 T 细胞积累和 RORg+ T 细胞增加，因此，在具体目标 1 中，Lechner 博士将。 使用小鼠模型和分析确定 RORg+ Th17 和 Tc17 以及 TPH 细胞在 IrAE 发育中的作用 患有 ICI 甲状腺炎的甲状腺浸润细胞与 HT 患者的比较 已知甲状腺缺乏自身抗体。 许多 ICI 甲状腺炎患者的抗原（例如甲状腺过氧化物酶甲状腺球蛋白）也表明免疫攻击 因此，在特定目标 2 中，Lechner 博士将识别 ICI 中的抗原靶点。 甲状腺炎，评估对这些抗原的免疫反应，并将它们与 HT 中的已知抗原进行比较。 Lechner 博士的工作旨在增进我们对甲状腺自身免疫性疾病潜在机制的理解 和检查点免疫治疗毒性，并获得成为独立研究者所需的技能。