Autoimmunity in Cardiopulmonary Toxicities from Radiotherapy andImmunotherapy

总结 胸部放疗和PD-1阻断免疫治疗后的心脏毒性主要是 影响生活质量和生存。因此，早期诊断测试和 致命毒性的干预。我们的建议旨在了解免疫机制， 可能危及生命的心肺毒性。我们建议在两种小鼠模型中研究毒性 和病人的血液样本。为了实现我们的目标，我们组建了一个合作团队， 在三个机构与一组专家顾问，以确定生物相关性， 治疗靶点来改善这些自身免疫毒性。我们之前的研究显示， 同时暴露于放射治疗和PD-1抑制的小鼠，我们发现这取决于两种治疗方法。 细胞因子IL-17 A和B细胞。由于Th 17/IL-17 A和体液免疫都涉及自身免疫性疾病， 我们假设毒性是由于PD-1引起的未经检查的适应性Th 17应答引起的， 阻断，与针对由促炎性B- 淋巴细胞我们将采用小鼠模型和药理学抑制剂来剖析潜在的 自身免疫机制和测量Th 17和B细胞反应的关键成分， 从接受联合收割机和免疫治疗的肺癌患者中收集血液样品。 目的1：研究IL-17 A/Th 17应答是否介导了细胞毒作用。我们假设 先天性和适应性免疫通过IL-17 A的连接而促成毒性。我们将产生KO小鼠 不能通过中性粒细胞或CD 4 T细胞产生IL-17 A。我们认为毒性是 当Th 17/IL-17 A在这些小鼠模型中钝化时，为了确定IL-17 A/Th 17是否可以被 作为毒性的预测生物标志物，我们将检测血清中Th 17/IL-17 A的动态变化， 我们病人的样本目的2：确定体液反应在介导 毒性我们假设促炎性Tbet+ B淋巴细胞驱动自身抗体的产生， 导致毒性。我们将使用Tbetflox/flox CD 19 cre小鼠作为我们的模型，其中成熟的Tbet+ B细胞被转染。 无托叶该方法将通过使用抗-CD 20的B细胞的药理学耗竭或通过 在野生型小鼠中用IVIg中和自身抗体。我们希望这些药物的毒性会减弱， 模型此外，我们将测试Th 17/IL-17 A的药理学抑制剂是否减少Tbet+ B细胞， 自身抗体最后，血液中自身抗体的上升将在小鼠和患者中作为替代物被捕获 因为毒性。我们在临床前模型中的基本机制的研究，结合患者的分析， 样本，将导致新的诊断早期发现和改善治疗严重心肺 毒性

Summary Cardiopulmonary toxicities following thoracic radiotherapy and PD-1 blocking immunotherapy have a major impact on quality of life and survival. Therefore, there is an unmet need to have early diagnostic test and intervention for fatal toxicities. Our proposal aims to understand immune mechanisms that modulate potentially life-threatening cardiopulmonary toxicities. We propose to study the toxicities in both mouse models and patients by analyzing blood samples. To achieve our goals, we have assembled a collaborative team across three institutions with a group of expert consultants in order to identify biological correlates and therapeutic targets to ameliorate these autoimmune toxicities. Our prior studies showed excessive mortality in mice simultaneously exposed to radiotherapy and PD-1 inhibition, which we show is dependent on both the cytokine IL-17A and the B-cell. Since both Th17/IL-17A and humoral immunity are implicated in autoimmune diseases, we hypothesize that toxicities result from the unchecked adaptive Th17 response due to PD-1 blockade, combined with autoantibodies against heart and lung tissues generated by the pro-inflammatory B- lymphocytes. We will employ mouse models and pharmacological inhibitors to dissect the underlying autoimmune mechanisms and measure key components of Th17 and B-cell response in prospectively collected blood samples from lung cancer patients undergoing combine radiotherapy and immunotherapy. Aim 1: To determine whether IL-17A/Th17 responses mediate the toxicities. We hypothesize that both innate and adaptive immunity contributes to the toxicities through the link of IL-17A. We will generate KO mice unable to produce IL-17A through either neutrophils or CD4 T cells. We expect that the toxicities are attenuated when Th17/IL-17A are blunted in these mouse models. To determine whether IL-17A/Th17 can be used as predictive biomarkers for the toxicities, we will examine dynamic changes of Th17/IL-17A in serum samples from our patients. Aim 2: To determine the role of humoral response in mediating the toxicities. We hypothesize that pro-inflammatory Tbet+ B-lymphocytes drive autoantibody production which results in the toxicities. We will use Tbetflox/flox CD19cre mice as our model, in which mature Tbet+ B cells are absent. This approach will be complemented by pharmacological depletion of B cells using anti-CD20 or by neutralizing autoantibodies with IVIg in wild-type mice. We expect that the toxicities are attenuated in these models. Furthermore, we will test whether pharmacological inhibitors of Th17/IL-17A reduce Tbet+ B cells and autoantibodies. Finally, the rise of autoantibodies in blood will be captured in mice and patients as a surrogate for the toxicities. Our study of basic mechanisms in preclinical models, combined with analysis of patient samples, will lead to novel diagnostics for early detection and improved therapies for severe cardiopulmonary toxicities.