Elucidating the Immune Landscape in Clonal Haematopoiesis of Indeterminate Potential and Progression to Haematological Malignancy

克隆性造血不确定潜能(CHIP)是一个术语，用于描述在其他正常血细胞中存在导致血癌的基因改变。作为衰老过程的一部分，芯片在正常人中是常见的。在70岁以上的人中，每10个人中就有1人患有此病。CHIP的存在增加了血癌的风险，如骨髓增生异常综合征(MDS)和急性髓系白血病(AML)，以及心脏病。然而，这种风险的增加相对较小。因此，重要的是要了解哪些患有CHIP的人患上这些更严重的疾病的风险最大，以及为什么。能够识别CHIP和那些最有可能演变为癌症的人的目标是找到避免或推迟这种情况发生的方法。这对MDS和AML至关重要，特别是对老年人，因为这些疾病是无法治愈的，因为治疗的毒性性质。对患者进行CHIP检测相对简单，但我们不太清楚哪些患者会进展为血癌。这一至关重要的知识在我们对芯片的理解中存在很大差距，因为我们无法向受影响的患者提供适当的进一步信息。人们对癌症越来越感兴趣的一个领域是了解我们自己的身体免疫系统如何对癌细胞做出反应(称为癌症免疫学)。癌细胞通常会发展出躲避免疫系统的方法，以帮助它们生长。在过去的几年里，已经开发出了新的治疗方法，可以帮助免疫系统发现并摧毁癌细胞，或者创造出专门针对癌细胞的人工修饰免疫细胞。对癌细胞(尤其是T细胞)的有效免疫反应是人体抵御癌症发展的最重要的防御措施。有趣的是，针对CHIP/AML相关突变的T细胞反应已经被发现。然而，免疫系统在帮助控制CHIP中的作用及其向MDS/AML的进展尚不清楚。我们认为，对CHIP细胞的主动免疫可能对MDS/AML患者具有保护作用。因此，该项目的目标是详细了解免疫细胞及其在CHIP患者中的工作原理。我们将调查是否可以识别芯片特异性T细胞反应，以及这些反应是否可以预测从芯片到MDS/AML的进展。该项目得益于获得一个独特的资源：英国老龄化纵向研究(ELSA)。ELSA是一项关于老龄化的长期研究(自2002年以来)。作为研究的一部分，参与者每隔一年接受一次关于他们健康和血液样本的采访。因此，它非常适合研究芯片及其随时间的进展/并发症。我们将对这些样本进行突变筛选，以识别使用芯片的个体，并评估芯片随着时间的推移如何进展。然后，我们将与ELSA一起，用芯片从特定个人身上收集新的血液样本，对免疫细胞进行更详细的分析。利用这些样本和主办机构在癌症免疫学方面的世界级专业知识，我们将在芯片中查看免疫系统中不同细胞的范围。特别是，我们将评估T细胞的类型和功能，以及这些细胞如何随着芯片的进展而变化。我们还将研究血液中其他类型的免疫细胞，这些细胞可能会被芯片改变。我们提出了一个特别令人兴奋和新颖的实验，使用突变特异性标记来分离携带芯片突变的血细胞，并将它们与正常细胞进行比较。鉴于老年人MDS/AML预后不良，本研究的长期目标是提高对CHIP生物学及其向MDS/AML进展的了解，推动该领域朝着旨在降低血癌和其他与芯片相关的健康问题的风险的策略迈进。

Clonal Haematopoesis of Indeterminant Potential (CHIP) is a term used to describe the presence of blood cancer-causing genetic alterations in otherwise normal blood cells. CHIP is a common finding in normal people as part of the ageing process. It is seen in 1 in 10 people over 70 years. The presence of CHIP increases the risk of blood cancers, such as myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) , as well as heart disease. However, this increase in risk is relatively modest. Therefore, it is important to understand which individuals with CHIP have the greatest risk of these more severe conditions and why.The goal of being able to identify CHIP and those at greatest risk of evolving into cancer is to find ways to avoid or delay this happening. This is vitally important in MDS and AML, especially in older people, as due to the toxic nature of the treatment these conditions are incurable. It is relatively straight forward to test patients for CHIP, however, we do not know much about which patients will progress to blood cancer. This vital knowledge is a big gap in our understanding of CHIP because we cannot provide appropriate further information to affected patients. An area of increasing interest in cancer is understanding how our own bodies immune system reacts to cancer cells (termed cancer immunology). Cancer cells commonly develop methods of hiding themselves from the immune system to help them grow. New treatments have been developed in the past few years that can help the immune system to see and destroy cancer cells, or create artificially modified immune cells that target the cancer cells specifically. Effective immune responses against cancer cells (particularly in 'T-cells'), are the most important defence that the body has against the development of cancer. Interestingly, T-cell responses directed against CHIP/AML-associated mutations have been found. However, the role of the immune system in helping to control CHIP, and its progression to MDS/AML are not clear. We think that active immunity towards CHIP cells may protect patients from developing MDS/AML. The goal of this project therefore is to understand in detail the immune cells and how they work in patients with CHIP. We will investigate if CHIP-specific T-cell responses can be identified and if these predict progression from CHIP to MDS/AML. This project benefits from access to a unique resource: the English Longitudinal Study of Ageing (ELSA). ELSA is a long-running study into ageing (since 2002). As part of the study, participants are interviewed about their health and blood samples taken every other year. It is therefore perfectly placed to investigate CHIP and its progression/complications over time. We will screen these samples for mutations to identify individuals with CHIP and assess how the CHIP progresses over time. In conjunction with ELSA, will with then collect new blood samples from specific individuals with CHIP for more detailed analysis of the immune cells.Using these samples and the world-class expertise in cancer immunology in the host institution, we will look at the range of different cells in the immune system in CHIP. Particularly we will assess the types and function of T-cells and how these change with CHIP progression. We will also look at other types of immune cells in the blood, that may be altered by CHIP. We propose a particularly exciting and novel experiment using mutation-specific markers to separate out the blood cells carrying the CHIP mutations to compare them to normal cells. Given the poor prognosis of MDS/AML in older people, the long-term aim of this research is to improve understanding of the biology of CHIP and its progression to MDS/AML, to progress the field towards strategies aimed at modifying the risk of developing of blood cancer and other CHIP-associated health problem.