Understanding immune-related toxicities through multifacet profiling

免疫检查点抑制剂疗法是一种新型的癌症治疗方法，它显著改善了许多广泛或局部晚期癌症患者的预后。免疫系统通常通过识别和破坏癌细胞来预防癌症。然而，许多类型的癌症使用机制来逃避这种免疫监视。他们这样做的一种方式是通过使用称为免疫检查点的细胞表面信号分子来降低抗癌免疫细胞的活性。当这些免疫检查点被癌细胞参与时，它们使免疫细胞失活。这使得肿瘤可以不受抑制地生长。免疫检查点抑制剂阻断这些免疫检查点以重新激活抗癌免疫细胞。鉴于它们的成功，这些药物已被许可用于治疗越来越多的癌症类型。它们在辅助治疗中的应用也在扩大，患者在手术后接受免疫治疗，以降低癌症复发的风险。因此，越来越多的患者接受这些药物治疗。不幸的是，免疫检查点抑制与潜在的严重副作用有关。这些被称为免疫相关不良事件（irAE）。它们是由免疫细胞的有害过度激活引起的，免疫细胞攻击健康组织而不是癌细胞。irAE影响高达95%的接受最强形式免疫疗法治疗的癌症患者，该疗法结合了两种免疫检查点抑制剂。高达50%的患者会发生irAE，需要使用强效免疫抑制类固醇治疗或停止免疫治疗。两者都有癌症预后不良的风险，而类固醇也会引起其他严重的副作用。因此，我们需要更好地了解irAE背后的机制，以开发更特异性地靶向irAE而不影响抗癌效果的改进治疗方法。目前，人们对irAE的发生机制和原因知之甚少。我们不知道为什么有些患者发生严重甚至致命的irAE，而另一些患者则根本没有发生irAE。我们也没有确定参与irAE的免疫细胞和信号分子的关键类型。这是迫切需要确定潜在的新的治疗靶点。我们的研究项目旨在解决这些关键问题。我们将使用来自接受免疫检查点抑制剂的患者的血液和组织样本。我们专注于皮肤，因为它是非常常见的irAE影响。第一个血液样本是在患者开始治疗之前采集的。然后，我们在治疗期间和发生irAE时重复采集样本。我们将确定与非irAE患者相比，irAE患者血液中出现的免疫细胞和信息分子类型。一个关键的假设是，irAE患者在控制其他“效应”免疫细胞活性的特定免疫细胞中存在缺陷。我们将评估的控制免疫细胞是T调节细胞，其控制细胞介导的免疫应答，以及滤泡T细胞，其控制抗体介导的免疫应答。我们将测量它们的数量，并测试来自irAE患者的细胞控制免疫激活的能力是否受损。来自有和没有皮肤irAE的患者的皮肤活检将使用称为单细胞RNA测序的强大技术进行分析。这使我们能够识别皮肤样本中的所有免疫细胞，以及哪些炎症信使通路在其中活跃。这可以导致识别新的治疗靶点，以关闭皮肤炎症。最后，我们将探讨是否有可能在开始免疫治疗前预测个体患者是否可能发生irAE。这有可能有助于个性化治疗。对irAE高风险患者可进行更密切的监测，或可能接受强度较低的治疗，以避免严重副作用。

Immune checkpoint inhibitor therapy is a new type of cancer treatment that has significantly improved the outcomes for many patients with widespread or locally advanced cancer. The immune system normally works to prevent cancer by recognising and destroying cancerous cells. However, many types of cancer use mechanisms to escape this immune surveillance. One way they do so is by reducing the activity of anti-cancer immune cells using cell-surface signalling molecules called immune checkpoints. When these immune checkpoints are engaged by cancer cells they render the immune cells inactive. This then allows tumours to grow unchecked. Immune checkpoint inhibitors block these immune checkpoints to reactivate anti-cancer immune cells. Given their success, these drugs have been licensed to treat an increasing range of cancer types. Their use is also expanding in the adjuvant setting, where patients receive immunotherapy after surgery to reduce the risk of their cancer returning. Thus, an ever-increasing number of patients receive these medications. Unfortunately, immune checkpoint inhibition is associated with potentially serious side effects. These are called immune-related adverse events (irAEs). They result from harmful overactivation of immune cells, which attack healthy tissues rather than cancer cells. irAEs affect up to 95% of cancer patients treated with the strongest form of immunotherapy, which combines two immune checkpoint inhibitors. Up to 50% of patients will experience irAEs that require either treatment with powerful immune-suppressing steroids or discontinuation of their immunotherapy. Both carry a risk of worse prognosis of their cancer, whilst steroids can also cause significant other side effects. We therefore require a better understanding of the mechanisms behind irAEs to develop improved treatments that target the irAE more specifically without compromising anti-cancer effects. Currently, how and why irAEs arise is very poorly understood. We do not know why some patients develop severe or even deadly irAEs whilst others develop no irAEs at all. We have also not identified the key types of immune cells and signalling molecules involved in irAEs. This is urgently required to identify potential new therapeutic targets. Our research project is designed to address these key issues. We will be working with blood and tissue samples from patients receiving immune checkpoint inhibitors. We are focussing on skin, as it is very commonly affected by irAEs. The first blood sample is taken before patients start treatment. We then take repeat samples during treatment and when irAEs develop. We will identify what types of immune cells and messaging molecules arise in the blood of irAE patients compared to non-irAE patients. One key hypothesis is that irAEs patients have a defect in specific immune cells, which control the activity of other "effector" immune cells. The controller immune cells we will assess are T-regulatory cells, which control cell-mediated immune responses, and follicular T-cells, which control antibody-mediated immune responses. We will measure their numbers and test whether cells from irAE patients are impaired in their ability to control immune activation. Skin biopsies from patients with and without skin irAEs will be analysed with a powerful technique called single cell RNA sequencing. This allows us to identify all the immune cells within the skin sample and what inflammatory messenger pathways are active in them. This can lead to the identification of novel therapeutic targets to switch the skin inflammation back off. Finally, we will explore whether it is possible to predict if an individual patient is likely to develop irAEs before they start immunotherapy. This has the potential to help personalise treatment. Patients at high risk of irAEs could be monitored more closely or potentially receive less intense treatment to avoid serious side effects.