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

项目摘要/摘要 这项提案描述了为Sang Kim博士的职业发展制定的严格培训计划 独立的医生兼科学家。 首席研究员是一位内科科学家，完成了他的免疫生物学博士学位和他的临床 耶鲁大学风湿病研究奖学金。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。他建议将他的培训扩展到 T细胞和癌症免疫学通过博士的指导下的强化培训研究经验。 Roza Nurieva，一位对T细胞在癌症中的作用拥有无与伦比的智力和技术洞察力的世界领导者 以及自身免疫性疾病。此外，由于肿瘤和宿主免疫系统的相互作用至关重要 在癌症免疫治疗引起的免疫相关不良事件(IrAEs)的发展中，以及因为 尖端基因组技术是理解免疫的复杂生物学的有力工具 在这个系统中，金博士还将有机会在金博士的指导下研究癌症/功能基因组学。 安德鲁·富特雷尔(共同初级导师)，世界著名的癌症基因组学科学家。 这项建议的研究目的是研究与免疫相关的关节炎的机制。 检查点抑制疗法(关节炎-IRAE)。这项提议的初步数据显示Th1的优势 关节炎患者的细胞特征-IRAE。此外，Th17细胞在与关节炎相关的疾病中被扩增。 联合应用PD-1和CTLA-4抑制剂治疗激素耐药。此外，金博士观察到， 在PD-1和PD-1联合作用下，偏斜状态下有更多的CD4T细胞极化为Th17细胞 CTLA-4抑制剂优于单独使用PD-1抑制剂。根据这些结果，金博士假设 Th1细胞在关节炎发病机制中起关键作用，Th17细胞在类固醇抵抗中起关键作用 联合应用PD-1和CTLA-4抑制剂诱导大鼠关节炎。为了解决这一假设，金博士将 研究导致关节炎发生的机制，特别是Th1/Tc1、Th17/Tc17和 调节性T细胞和确定机制驱动的生物标志物来预测关节炎的发展，反映了 关节炎疾病活动性，并预测类固醇抗药性。 这项建议为Sang Kim博士成为风湿并发症专家提供了一种培训工具 由基于免疫的癌症治疗引起的，一个爆炸性的新兴和具有挑战性的临床实体 风湿病。

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.