B cell function and risk of progression in smouldering myeloma

多发性骨髓瘤(MM)是一种血液和骨髓癌症，在英国任何时候都会影响24000名患者。多发性骨髓瘤患者的骨髓浆细胞生长异常。这些癌细胞以不受控制的方式生长，可能会导致肾衰竭、骨痛和骨折，以及由低红细胞引起的贫血等症状。虽然存在许多新的治疗方法，但多发性骨髓瘤仍然无法治愈。多发性骨髓瘤始于一种名为阴燃骨髓瘤的癌前状态，在骨髓中检测到异常浆细胞，但患者没有症状。目前，这些患者没有得到治疗，但受到了监测，因为随着时间的推移，许多人会发展为有症状的疾病，需要化疗，但其他人不会。虽然有兴趣治疗这些患者，看看我们是否可以延缓进展到活动期MM，但我们并不完全理解为什么有些人进展，另一些人没有，以预测哪些患者将需要治疗。此外，如果我们了解了导致隐匿性骨髓瘤疾病进展的因素，我们希望能够给予有针对性的治疗来阻止活动性骨髓瘤的发展。我们现在了解到，当癌细胞逃离免疫细胞的控制时，就会发生癌前疾病向癌症的进展，而这些免疫细胞在控制没有进展的患者中阴燃的浆细胞方面发挥了作用。但我们不了解这里不同类型的免疫细胞的功能。大多数研究都集中在一种名为T细胞的白细胞上，这种细胞可以杀死癌细胞。B细胞是另一种免疫细胞，通过产生抗体来对抗感染。我们知道多发性骨髓瘤患者的B细胞通常是有缺陷的，对感染或疫苗接种不能产生正常水平的抗体。因此，多发性骨髓瘤患者经常会受到感染。浆细胞是骨髓瘤中的癌细胞，也与B细胞有关。我们不知道骨髓中的B细胞如何随着骨髓瘤的发展而变化，尽管我们有证据表明，在阴燃的骨髓瘤患者中，B细胞的数量已经减少。我们也不知道骨髓B细胞是否在癌症的发展中起到了作用，或者它们是否具有保护性。存在不同的B细胞亚型，其中一些类型已被证明对其他癌症具有保护作用或有害作用。我们已经开始观察阴燃骨髓瘤患者的B细胞，我们发现这些细胞的不同亚家族有明显的变化。我们认为，这些变化为B细胞如何在这种癌症的发展中发挥作用提供了线索。这个项目的目标是：1.确定阴燃骨髓瘤中B细胞的特征2.观察这些B细胞在阴燃骨髓瘤中的功能，与来自健康人的B细胞进行比较3.在骨髓瘤小鼠模型中重建这种功能障碍，以研究B细胞如何影响骨髓瘤的发展。这将在伦敦大学学院与英国的其他合作者一起进行。患者样本是从一项全国性的临床试验中收集的，患者在采集血液或骨髓时同意额外的样本用于研究。这些患者选择同意这项试验，因为他们想帮助进一步了解这种疾病。将对骨髓瘤的小鼠模型进行研究，以跟踪B细胞行为和数量的变化。这项工作的目标是试图了解我们是否可以更准确地预测哪些阴燃骨髓瘤患者将进展为MM，并了解B细胞在这一进展中所起的作用。我们的工作将发现，某些B细胞的变化是否可以发出更大的进展风险的信号，以及如何利用这一知识来设计治疗方案，以防止从阴燃骨髓瘤到活动期MM的进展。

Multiple myeloma (MM) is a cancer of the blood and bone marrow which affects 24,000 patients in the UK at any one time. Patients with MM have an abnormal growth of plasma cells in their bone marrow. These cancerous plasma cells grow in an uncontrolled manner and can cause symptoms such as kidney failure, bone pain and fractures, and anaemia caused by low red blood cells. Although many new treatments exist, MM remains incurable. MM starts as a pre-cancerous condition called smouldering myeloma, where abnormal plasma cells are detected in the bone marrow, but patients do not have symptoms. Currently these patients are not treated but are monitored as many will progress to symptomatic disease over time and need chemotherapy, however others will not. Although there is interest in treating these patients to see if we can delay progression to active MM, we do not have a full understanding of why some people progress, and others don't, to predict which patients will need treatment. In addition, if we understand the factors that contribute to disease progression from smouldering myeloma we hope that targeted treatments could be given to stop active myeloma developing. We now understand that progression of pre-malignant conditions to cancer occurs when cancer cells have escaped from the control of immune cells, and that these immune cells play a part in controlling the smouldering plasma cells in patients who do not progress. But we do not understand the functions of the different types of immune cells here. Most research has focussed on a type of white blood cells called T cells which can kill cancer cells. B cells are another type of immune cell, that fight infection by making antibodies. We know that the B cells in MM patients are often defective, and do not make normal levels of antibodies in response to infection or vaccination. Thus MM patients often get frequent infections. Plasma cells, which are the cancer cell in myeloma, are also related to B cells. We do not understand how B cells in the bone marrow change as myeloma develops, although we have evidence that they are already reduced in number in smouldering myeloma patients. We also do not understand whether marrow B cells play a part in the development of the cancer or if they can be protective. Different subtypes of B cells exist and some of these types have been shown to be protective or harmful in other cancers. We have started to look at the B cells in patients with smouldering myeloma, and we have found that there are marked changes in distinct sub-families of these cells. We believe that these changes hold clues as to how B cells may play a part in the development of this cancer. The aims of this project are: 1. Characterise the B cell populations in smouldering myeloma 2. Look at how these B cells function in smouldering myeloma, compared to B cells from healthy people 3. Recreate this dysfunction in a mouse model of myeloma to study how B cells affect the development of myeloma. This will be carried out at UCL, with other collaborators in the UK. Patient samples are collected from a national clinical trial where patients consent for extra samples to be used for research when they are having blood or bone marrow taken. These patients have chosen to consent to the trial because they want to help further understanding of this disease. A mouse model of myeloma will be studied to follow the changes in B cell behaviour and numbers. The goal of this work is to try and understand if we can predict more accurately which patients with smouldering myeloma will progress to MM, and to understand what part B cells play in this progression. Our work will discover if changes in certain B cells can signal a greater risk of progression, and how to use this knowledge to design treatments to prevent progression from smouldering myeloma to active MM.