Characterization of Altered Immunity in Patients with Inflammatory Arthritis Induced by Immune Checkpoint Inhibitor Therapy

项目概要/摘要 该提案描述了一个严格的培训计划，以促进金尚博士的职业发展， 独立的物理学家和科学家 主要研究者是一位医生兼科学家，完成了免疫生物学博士学位和临床研究 耶鲁大学的风湿学奖学金。他的职业目标是成为一名独立调查员， 基于免疫的癌症疗法引起的风湿性并发症。他建议扩大他的训练， T细胞和癌症免疫学，通过密集的培训研究经验的指导下，博士。 Roza Nurieva，世界领先者，对T细胞在癌症中的作用具有无与伦比的知识和技术洞察力 和自身免疫性疾病。此外，由于肿瘤和宿主免疫系统的相互作用至关重要， 在癌症免疫治疗诱导的免疫相关不良事件（irAE）的发生中， 尖端的基因组技术是理解免疫系统复杂生物学的有力工具， 系统，金博士也将有机会研究癌症/功能基因组学博士的指导下， Andrew Futreal（共同主要导师），世界著名的癌症基因组学科学家。 本课题的研究目的是探讨免疫相关性关节炎的发病机制。 检查点抑制剂治疗（关节炎-irAE）。该提议的初步数据揭示了Th 1的优势 关节炎irAE患者的细胞特征。此外，Th 17细胞在关节炎相关性关节炎中扩增， PD-1和CTLA-4抑制剂联合治疗伴类固醇耐药。此外，金博士还观察到， 在组合的PD-1存在下，更多的CD 4 + T细胞在倾斜条件下极化为Th 17细胞， CTLA-4抑制剂比单独的PD-1抑制剂存在下更有效。根据这些结果，金博士假设， Th 1细胞在关节炎-irAE的发病机制中起关键作用，Th 17细胞在类固醇耐药中起关键作用。 联合PD-1和CTLA-4抑制剂诱导的关节炎-irAE。为了解决这个假设，金博士将 研究导致关节炎-irAE发展的机制，特别关注Th 1/Tc 1，Th 17/Tc 17， 调节性T细胞，并确定机制驱动的生物标志物，以预测关节炎-irAE的发展，反映 关节炎疾病活动，并预测类固醇抵抗。 这一建议作为一个培训工具博士金相成为风湿并发症的专家 由基于免疫的癌症治疗引起，这是一种爆炸性新兴和具有挑战性的临床实体， 风湿病学

PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program for the career development of Dr. Sang Kim as an independent physician-scientist. The principal investigator is a physician-scientist who completed his PhD in immunobiology and his clinical rheumatology fellowship at Yale University. His career goal is to become an independent investigator studying rheumatic complications induced by immune-based cancer therapeutics. He proposes to expand his training in T cell and cancer immunology through an intensive training research experience under the mentorship of Dr. Roza Nurieva, a world leader with unparalleled intellectual and technical insight into the role of T cells in cancers and autoimmune diseases. In addition, because interactions of tumors and the host immune system are critical in development of immune-related adverse events (irAEs) induced by cancer immunotherapy, and because cutting-edge genomic technologies are a powerful tool in understanding the complex biology of the immune system, Dr. Kim will also have an opportunity to study cancer/functional genomics under the mentorship of Dr. Andrew Futreal (co-primary mentor), a world-renowned scientist in cancer genomics. The research objective of this proposal is to investigate mechanisms of arthritis associated with immune checkpoint inhibitor therapy (arthritis-irAE). Preliminary data for this proposal revealed the predominance of Th1 cell signatures in the patients with arthritis-irAE. In addition, Th17 cells were expanded in arthritis associated with combined PD-1 and CTLA-4 inhibitor therapy with steroid resistance. Furthermore, Dr. Kim observed that more CD4+ T cells were polarized into Th17 cells in skewing conditions in the presence of combined PD-1 and CTLA-4 inhibitors than in the presence of PD-1 inhibitor alone. From these results, Dr. Kim hypothesizes that Th1 cells play a critical role in the pathogenesis of arthritis-irAE and that Th17 cells are pivotal in steroid-resistant arthritis-irAE induced by combined PD-1 and CTLA-4 inhibitors. To address the hypothesis, Dr. Kim will investigate mechanisms leading to development of arthritis-irAE, with special focus on Th1/Tc1, Th17/Tc17, and regulatory T cells, and determine mechanism-driven biomarkers to predict development of arthritis-irAE, reflect arthritis disease activity, and predict steroid resistance. This proposal serves as a training vehicle for Dr. Sang Kim to become an expert in rheumatic complications induced by immune-based cancer therapy, an explosively emerging and challenging clinical entity in rheumatology.