B cell depletion to prevent autoimmunity

项目摘要 免疫相关不良事件（IRAE）仍然是最佳联合应用的主要障碍 检查点封锁在人类癌症中的作用更深入地了解这些IRAE的机制， 特别是潜在的细胞和基因组途径和抗原靶点对于开发最佳的 预防和治疗这些AE的策略。这个应用程序代表了两个 具有癌症免疫学（KD）和人类自身免疫（IS）经验的研究人员研究了 IRAE中的B细胞。它直接建立在我们先前评估患者早期免疫学变化的研究基础上 接受免疫检查点封锁，以及对改变的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治疗导致了一种独特的模式， B细胞的变化，特别是涉及CD 21 lo B细胞亚群和浆母细胞。我们还确定 自身免疫性疾病如狼疮中B细胞的不同表观遗传和转录特征。我们 一个假设是，自身反应性B细胞的预先存在的变化将识别出处于早期IRAE风险中的患者。我们 进一步证实CCB诱导的致病性B细胞的扩增是由表观遗传的参与介导的， 和类似于在天然发生的自身免疫中观察到的那些的转录组程序。B细胞已经 被认为在癌症中同时发挥促肿瘤和抗肿瘤作用。为了特异性地分离B细胞在 IRAE，我们将在随机临床试验的背景下评估致病性B细胞和浆母细胞的变化。 在接受CCB的黑色素瘤患者中特异性耗竭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学改变是否确定了 存在CCB诱导的irAE风险并通过Rituxan恢复正常的患者 目标2.评价利妥昔单抗介导的致病性B细胞耗竭及其对irAE的贡献 在CCB之后 目标3.评价B细胞耗竭是否导致循环或肿瘤浸润性T细胞的改变， 接受CCB的患者的细胞。 总之，这些研究将提供直接的见解，B细胞在患者中的相对贡献， CCB对肿瘤免疫相互作用和患者结局的有利和不利影响。 直接了解人体内这些细胞间的相互作用对于开发合理的方法， 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.