Understanding the pathogenesis of Epstein-Barr virus-associated complications arising in patients treated with immune checkpoint regulators

免疫检查点调节器(ICR)是一种革命性的新型治疗方法，它通过操纵免疫系统来抗击癌症。虽然ICR方案改善了癌症患者的预后，但它们与许多被称为免疫相关不良事件(IRAE)的自身免疫并发症有关。免疫相关性结肠炎(Ircoltis)是影响患者最常见的疾病之一，在大约1-5%的患者中，会导致严重的肠道炎症和穿孔。结肠穿孔是一种严重的危及生命的急症，对患者有潜在的长期影响。众所周知，细菌可以调节免疫检查点治疗的效果和并发症。病毒对iCR预后的影响尚不清楚。在一项对诊断组织标本的小型回顾性研究中，我们发现ICR治疗的irCol患者中有一部分在胃肠道过程中显示出多处溃疡。进一步调查，这些溃疡含有感染了EB病毒(EBV)的免疫细胞。这一实体称为EBV黏膜皮肤溃疡(EBVMCU)。关键的是，在13例显示EBVMCU的病例中，有4例都与严重的炎症和穿孔有关。研究结果表明，ICR或用于治疗结肠炎的抗免疫药物影响免疫系统控制EBV的方式，EBV在95%的人口中潜伏存在。这是有史以来第一个病毒与ICR治疗相关并发症之间联系的例子。随着新的ICR药物的开发，这种相互作用可能对ICR在临床上的使用变得更加重要。本研究的目的是：1.分析ICR相关性EBVMCU的临床病程和病理特点。2.研究ICR治疗开始时血液和组织中的免疫系统的变化。计划第1部分：我们将描述在ICR治疗的患者中发生的EBVMCU的特征。我们将检查肠炎后肠穿孔患者的多余诊断组织。我们将进行以下检测：i.EBV：检测EBV.ii的存在。基因：我们将观察一些ICR的靶标CTLA-4基因的变异是否会影响iCR.iii中EBVMCU的发育。我们将检查EBVMCU病变的细胞组成和免疫细胞，这将使我们能够确定EBVMCU在iColtis中的存在，并为这些病变的发展提供洞察力。第二部分：我们将跟踪50名开始接受ICR治疗的患者，并测量ICR对免疫系统的影响，特别是EBV的控制。这将提供有关ICRs对人类病毒的影响以及对控制它们至关重要的免疫反应的新信息。这项研究将为EBV免疫的调控提供有价值的见解，并可能对IRAE的管理产生临床影响。

Immune checkpoint regulators (iCR) are a revolutionary new class of treatment which manipulate the immune system to fight cancer. Whilst iCR regimens have yielded improved outcomes for patients with cancer, they are associated with a number of autoimmune complications termed 'immune-related adverse events' (irAE). One of the commonest irAE to affect patients is immune related colitis (irColitis), which in approximately 1-5% of patients, will result in severe inflammation of the bowel and perforation. Colonic perforation is a serious and life threatening emergency which has potential long term implications for patients. It is known that bacteria can modulate the effects and complications of immune checkpoint therapy. Nothing is known about the effect of viruses on outcome following iCR.In a small retrospective study of diagnostic tissue specimens, we found a proportion of iCR treated patients with irCol showed multiple ulcerations along the course of their gastrointestinal tract. On further investigation, these ulcerations contained immune cells infected with the Epstein-Barr virus (EBV). This entity is called EBV mucocutaneous ulcer (EBVMCU). Critically, the 4 of 13 cases which showed EBVMCU were all associated with severe inflammation and perforation.The findings suggest the either iCR, or the anti-immune drugs used to treat colitis, affects the way the immune system control EBV, which is latently present in 95% of the population. This is the first ever example of a link between viruses and complications related to iCR treatment. As new iCR drugs are developed, it is possible that such interactions will become ever more important to how iCRs are used clinically. The aim of this study is to: 1. Characterise the clinical course and pathological features of iCR associated EBVMCU. 2. Study the changes in the immune system in blood and tissue that occur upon commencement if iCR therapy, development of irColitis.PlanPart 1: We will characterise the features of EBVMCU that occur in patients treated on iCR therapy. We will examine surplus diagnostic tissue from patients who have suffered bowel perforated following irColitis. We will perform the following tests:i. EBV: Test for the presence of EBV.ii. Genes: we will see if variations in the CTLA-4 gene, the target of some iCR, effect EBVMCU development in iCR.iii. We will examine the cellular composition and the immune cells of the EBVMCU lesions.This will enable us to establish the incidenece of EBVMCU in irColitis and provide insight into how these lesions develop. Part 2: We will follow 50 patients started on iCR therapy and measure a the effect iCR has on the immune system, specifically, the control of EBV. This will provide new information on the effects of iCRs on human viruses and the immune responses that is essential for controlling them. The study will provide a valuable insight into the regulation of EBV immunity and could have clinical consequences as to how irAE are managed.