B cell depletion to prevent autoimmunity

项目总结 免疫相关不良事件(IRAE)仍然是最佳联合应用的主要障碍 人类癌症中的检查站封锁。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和抗原靶点对于开发出最佳的 预防和治疗这些不良事件的策略。此应用程序代表两个应用程序之间的协作 在癌症免疫学(KD)和人类自身免疫(IS)方面有经验的研究人员调查 IRAE中的B细胞。它直接建立在我们先前评估患者早期免疫变化的研究基础上。 接受免疫检查点阻断，以及改变B细胞分化和潜在功能的研究 人类自身免疫性疾病。在这些研究中，我们观察到CCB疗法导致了一种独特的模式 B细胞的变化，特别是涉及CD21lo B细胞亚群和浆母细胞。我们还确认了 狼疮等自身免疫性疾病中B细胞明显的表观遗传和转录特征。我们的 假设自身反应性B细胞的预先存在的变化将识别早期IRAE的风险患者。我们 进一步假设CCB诱导的致病B细胞的增殖是由表观遗传学参与介导的 转录程序类似于自然发生的自身免疫中观察到的程序。B细胞已经被 被认为在癌症中既有促肿瘤作用，也有抗肿瘤作用。为了特异性地分离B细胞在体内的作用 IRAES，我们将在随机临床的背景下评估致病B细胞和浆母细胞的变化 在接受CCB治疗的黑色素瘤患者中特异性去除B细胞的试验。该项目的具体目标是： 目的1.评估B细胞亚群中先前存在的转录和表观遗传改变是否能识别 有CCB诱导的irAEs风险并经利妥昔单抗正常化的患者 目的2.评价利妥昔单抗对致病B细胞的去除作用及其对irAEs的影响 继建行之后。 目的3.评估B细胞耗尽是否会导致循环或肿瘤浸润性T细胞的改变 经皮冠状动脉旁路移植术患者的细胞。 总之，这些研究将提供对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预后的有利和不利影响。 直接了解人类体内的这些细胞相互作用对于开发合理的方法来 防止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.