Unravelling the role of CD8+ T-cells in immune checkpoint inhibitor induced colitis

免疫系统在抵御包括癌症在内的疾病方面发挥着核心作用。这是通过大量免疫细胞的协调实现的，包括一种名为T细胞(免疫系统的“将军”)的亚群，它识别和协调对有问题的细胞的破坏。为了区分体内的正常细胞和“外来”细胞，免疫系统使用“检查点”--T细胞上的分子充当免疫系统的刹车，需要激活才能启动免疫反应。癌细胞利用这些检查点来避免免疫系统的攻击。免疫检查点抑制剂(ICPI)是针对这些检查点的药物，可以解除免疫系统的“刹车”，重新唤醒免疫系统，并使癌症治疗发生了革命性的变化。此类药物的例子包括ipilimumab和nivolumab，它们已被证明可以提高晚期癌症患者的存活率，包括皮肤黑色素瘤、非小细胞肺癌、肾癌、膀胱癌和霍奇金淋巴瘤。越来越多的证据表明，与单独治疗相比，ipilimumab和nivolumab联合治疗能诱导更有效的抗肿瘤反应。预计在接下来的几年里，这些药物将被批准用于治疗其他类型的癌症。然而，一个重要的考虑是ICPI与特定毒性的关联，其中以腹泻和结肠炎(肠道炎症)形式的胃肠道(GI)毒性最严重。在接受更有效的联合治疗的患者中，高达50%的患者会发生ICPI引起的结肠炎，可能会导致严重的疾病，有时会导致住院，如果不及时治疗，甚至死亡。这也是ICPI停产的最常见原因。由于缺乏对疾病背后的细胞和分子过程的了解，成功和及时的治疗受到限制，虽然似乎与其他形式的结肠炎有一些相似之处，如炎症性肠病(IBD)，但总的来说，它可能是一个独特的实体。虽然许多患者接受大剂量类固醇和/或额外的免疫抑制治疗，但这些治疗仍充满进一步的副作用，如严重感染。本研究的目的是确定介导ICPI相关性结肠炎的免疫学途径，并确定治疗的生物靶点，以期减轻疾病的严重程度，避免中断生命，延长癌症治疗。有新的证据表明，T细胞的一个亚群，即CD8+细胞，是炎症的关键驱动因素，然而，调节其激活的途径在很大程度上尚不清楚。为了提供进一步的见解，我正在与盖伊医院和皇家马斯登医院的国际知名癌症中心合作，接触接受联合治疗的患者，这些患者随后会出现腹泻或结肠炎。我将使用尖端实验室技术分析血液样本和结肠组织(当患者进行常规结肠镜检查以评估他们的疾病时)，并将其与健康患者和IBD患者进行比较。此外，我将使用结肠器官模型系统深入研究肠壁细胞(构成身体与外部环境之间的屏障)与CD8+细胞之间的相互作用。这些是在体外生产的器官的3D微型和简化版本，显示了逼真的微观解剖结构，并提供了关于免疫细胞/肠壁环境的非常丰富的信息。重要的是，为了减少CD8+细胞不是ICPI诱导的结肠炎的关键细胞的可能性，我还将捕获有关替代免疫细胞和D途径的数据。

The immune system plays a central role in defence against disease, including cancer. This is achieved by coordination of numerous immune cells, including a subset called T-cells (the 'generals' of the immune system), which identify and co-ordinate the destruction of faulty cells. To differentiate between normal cells in the body and "foreign" cells, the immune system uses "checkpoints" - molecules on T-cells that act as a brake on the immune system and require activation to initiate an immune response. Cancer cells exploit these checkpoints to avoid being attacked by the immune system. Immune check point inhibitors (ICPIs) are drugs that target these checkpoints, to release the 'brakes' and 're-awaken' the immune system and have revolutionized cancer therapy. Examples of such drugs includes ipilimumab and nivolumab, which have been proven to increase survival in patients with advanced cancer including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, and Hodgkin's lymphoma. There is increasing evidence that combination therapy with ipilimumab and nivolumab induces a more effective anti-tumour response, than single therapy alone. It is anticipated that over the next few years, these agents will be approved for treatment of other types of cancer. However, an important consideration is the association of ICPIs with specific toxicities, of which gastrointestinal (GI) toxicity in the form of diarrhoea and colitis (inflammation of the gut) is the most serious. Occurring in up to 50% of patients receiving the more efficacious combination treatment, ICPI-induced colitis can incur significant illness, sometimes leading to hospital admission and even death if not promptly treated. It is also the most common cause of ICPI discontinuation. Successful and timely management is limited by a lack of understanding of the cellular and molecular processes underlying the disease, and whilst there appears to be some similarities with other forms of well-studied colitis such as inflammatory bowel disease (IBD), overall it is probably a distinct entity. Although many patients are treated with high dose steroids and/or additional immunosuppression therapy, these are fraught with yet further sides effects such as serious infections.The aim of the current research is to determine the immunological pathways mediating ICPI-related colitis and identify biological targets for therapy with a view of reducing the severity of this disease and avoiding discontinuation of life prolonging cancer treatment. There is emerging evidence that a subset of T-cells, known as CD8+ cells, are key drivers of inflammation, however the pathways mediating their activation are largely unknown. To provide further insights, I am collaborating with the internationally renowned cancer centres at Guy's Hospital and the Royal Marsden Hospital to access patients treated with combination therapy, and who then develop diarrhoea or colitis. I will analyse blood samples and colonic tissue (taken when patients have a routine colonoscopy for assessment of their disease) using cutting edge laboratory techniques, and compare this to healthy patients and those with IBD. Additionally, I will study interactions between cells of the gut wall (which form the barrier between the body and external environment) and CD8+ cells in great depth using a colonic organoid model system. These are 3D miniaturized and simplified versions of an organ produced in vitro, that show realistic micro-anatomy and provide very rich information about the immune cell/gut wall environment. Importantly, to mitigate against the possibility that CD8+ cells are not the key cells implicated in ICPI- induced colitis, I will also be capturing data on alternative immune cells snd pathways.