(PQ8) Predictive biomarkers for the onset of immune-related adverse events associated with PD-1 blockade

项目摘要 拟议的研究，免疫相关不良事件发生的预测性生物标记物 通过PD-1阻断，回答了NCI的挑衅性问题8(PQ8)：什么是预测生物标志物 与检查点抑制相关的免疫相关不良事件的发生，它们是否与 疗效的标志？ 程序性细胞死亡-1(PD-1)是T细胞中一种重要的抑制性受体。阻断PD-1的抗体 增强抗肿瘤免疫反应，代表了一种强大的治疗模式。目前有 超过400项针对PD-1的临床试验，突显了其在癌症免疫治疗中的新兴潜力。 不幸的是，每4名接受抗PD-1治疗的患者中就有1人出现免疫相关不良事件(IrAEs)， 包括自身免疫力。因此，阐明免疫耐受崩溃的机制，从而导致 接受免疫检查点抑制剂(如抗PD-1)治疗的癌症患者的过度炎症， 提供了一个了解irAEs的分子基础和确定可预测的 为了开发更安全的下一代免疫疗法，irAEs的生物标记物。为了实现这一目标， 了解PD-1阻断如何重塑稳态T细胞反应至关重要。我们打算揭开 日本血吸虫抗原性T细胞的谱系多样性和特异性基因表达特征 接受抗PD-1治疗的患者，通过两个特定的目的：1)确定T细胞特异性基因的表达 区分在抗PD-1治疗后出现irAEs的患者的特征；以及2)测试 假设抗PD-1治疗降低了发生irAEs患者的T细胞多样性。我们 预计我们的发现将阐明T细胞谱系转变和T细胞谱系的分子复杂性 IrAEs发育过程中的信号动力学。在初步数据的支持下，该项目将应用新的 揭示irAEs背后的分子机制的方法。拟议的项目将结合 抗PD-1抗体治疗肺癌患者T细胞的转录和克隆谱分析 阐明免疫治疗中自我耐受崩溃的机制。在建议的两年内，我们会 在irAEs环境中检测PD-1相关的信号簇通路。这些研究将揭示 IrAEs的免疫发病机制，并可能揭示irAEs的预测性和严重性生物标志物。

PROJECT ABSTRACT The proposed study, Predictive biomarkers for the onset of immune-related adverse events associated with PD-1 blockade, addresses NCI’s Provocative Question 8 (PQ8): What are the predictive biomarkers for the onset of immune-related adverse events associated with checkpoint inhibition, and are they related to markers for efficacy? Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies that block PD-1 augment anti-tumor immune responses and represent a powerful therapeutic paradigm. There are currently over 400 clinical trials targeting PD-1, highlighting its emerging potential in cancer immunotherapy. Unfortunately, 1 in 4 patients who receive anti-PD-1 treatment develop immune-related adverse events (irAEs), including autoimmunity. As such, elucidating the mechanisms of immune-tolerance breakdown, which lead to excessive inflammation in cancer patients treated with immune-checkpoint inhibitors (such as anti-PD-1), presents a formidable opportunity to understand the molecular underpinnings of irAEs and to identify predictive biomarkers of irAEs in order to develop safer next-generation immunotherapies. To achieve this goal it is essential to understand how PD-1 blockade reshapes homeostatic T cell responses. We propose to uncover the repertoire diversity and the specific gene expression signatures of antigen-experienced T cells from patients undergoing anti-PD-1 therapy, via two Specific Aims: 1) to define T cell-specific gene expression signatures that distinguish patients who develop irAEs following anti-PD-1 therapy; and 2) to test the hypothesis that anti-PD-1 therapy decreases T cell repertoire diversity in patients who develop irAEs. We anticipate that our findings will shed light on the molecular complexity of both T cell repertoire transition and signaling dynamics during the development of irAEs. Supported by preliminary data, this project will apply new approaches to uncover the molecular mechanisms underlying irAEs. The proposed project will combine transcriptional and clonal repertoire analyses of T cells from lung cancer patients treated with anti-PD-1, to elucidate mechanisms of self-tolerance breakdown in immunotherapies. Within the proposed two years, we will examine PD-1 associated signaling clusters pathways in the setting of irAEs. These studies will reveal the immuno-pathogenesis of irAEs and will likely reveal both predictive and severity biomarkers for irAEs.