B cell depletion to prevent autoimmunity

项目概要 免疫相关不良事件（IRAE）仍然是组合药物最佳应用的主要障碍 人类癌症中的检查点封锁。更深入地了解这些 IRAE 背后的机制，以及 特别是潜在的细胞和基因组途径以及抗原靶标对于开发最佳的 预防和治疗这些 AE 的策略。该应用程序代表了两个人之间的协作努力 具有癌症免疫学 (KD) 和人类自身免疫 (IS) 经验的研究人员来研究 IRAE 中的 B 细胞。它直接建立在我们之前评估患者早期免疫变化的研究的基础上 正在进行免疫检查点封锁，以及改变 B 细胞分化和功能的研究 人类自身免疫性疾病。在这些研究中，我们观察到 CCB 疗法会导致一种独特的模式 B 细胞的变化，特别是涉及 CD21lo B 细胞亚群和浆母细胞的变化。我们还确定了 狼疮等自身免疫性疾病中 B 细胞的独特表观遗传和转录特征。我们的 假设是，自身反应性 B 细胞中预先存在的变化将识别出处于早期 IRAE 风险的患者。我们 进一步推测 CCB 诱导的致病性 B 细胞的扩增是通过表观遗传的参与介导的 和类似于自然发生的自身免疫中观察到的转录组程序。 B细胞已 提议在癌症中发挥促肿瘤和抗肿瘤作用。为了特异性分离 B 细胞的作用 IRAE，我们将在随机临床背景下评估致病性 B 细胞和浆母细胞的变化 一项专门消除接受 CCB 的黑色素瘤患者 B 细胞的试验。该项目的具体目标是： 目标 1. 评估 B 细胞亚群中预先存在的转录和表观遗传改变是否可识别 存在 CCB 诱导的 irAE 风险并通过 Rituxan 恢复正常的患者 目标 2. 评估 Rituxan 介导的致病性 B 细胞耗竭及其对 irAE 的贡献 继CCB之后。 目标 3. 评估 B 细胞的消耗是否会导致循环或肿瘤浸润 T 细胞的改变 接受 CCB 的患者体内的细胞。 这些研究将共同提供关于 B 细胞在接受治疗的患者中的相对贡献的直接见解。 CCB 对肿瘤免疫相互作用和患者结果的有利和不利影响。 直接了解人类的这些细胞相互作用对于开发合理的方法至关重要 预防IRAE。

PROJECT SUMMARY Immune related adverse events (IRAEs) remain a major obstacle to optimal application of combination checkpoint blockade in human cancer. Deeper understanding of the mechanisms underlying these IRAEs, and in particular underlying cellular and genomic pathways and antigenic targets is essential to develop optimal strategies to prevent and treat these AEs. This application represents a collaborative effort between two investigators with experience in cancer immunology (KD) and human autoimmunity (IS) to investigate the role of B cells in IRAEs. It builds directly on our prior studies evaluating early immunologic changes in patients undergoing immune checkpoint blockade, as well studies of altered B cell differentiation and function underlying human autoimmune disorders. In these studies, we have observed that CCB therapy leads to a distinct pattern of changes in B cells, particularly involving CD21lo B cell subset and plasmablasts. We have also identified distinct epigenetic and transcriptional signatures of B cells in autoimmune disorders such as lupus. Our hypothesis is that preexisting changes in autoreactive B cells will identify patients at risk for early IRAEs. We further posit that CCB-induced expansion of pathogenic B cells is mediated by the engagement of epigenetic and transcriptomic programs akin to those observed in naturally occurring autoimmunity. B cells have been proposed to play both a pro- and anti-tumor role in cancer. In order to specifically isolate the effect of B cells in IRAEs, we will evaluate changes in pathogenic B cells and plasmablasts in the context of a randomized clinical trial to specifically deplete B cells in melanoma patients undergoing CCB. The specific aims of the project are: Aim 1. To assess whether pre-existing transcriptional and epigenetic alterations in B cell subsets identify patients at risk for CCB-induced irAEs and are normalized by Rituxan Aim 2. To evaluate Rituxan-mediated depletion of pathogenic B cells and their contribution to irAEs following CCB. Aim 3. To evaluate whether depletion of B cells leads to alterations in circulating or tumor-infiltrating T cells in patients undergoing CCB. Together these studies will provide direct insights into the relative contribution of B cells in patients undergoing CCB, both in terms of favorable as well as adverse impact on tumor-immune interactions and patient outcome. Understanding these cellular interactions directly in humans is essential for developing rational approaches to prevent IRAEs.