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

不确定潜能的克隆性造血（CHIP）是一个术语，用于描述在其他正常血细胞中存在导致血液癌症的遗传改变。CHIP是正常人衰老过程中的常见发现。在70岁以上的人中，每10人中就有1人。CHIP的存在增加了血液癌症的风险，如骨髓增生异常综合征（MDS）和急性髓性白血病（AML），以及心脏病。然而，这种风险的增加相对温和。因此，重要的是要了解哪些CHIP患者最有可能患上这些更严重的疾病，以及为什么。能够识别CHIP和那些最有可能演变成癌症的人的目标是找到避免或延迟这种情况发生的方法。这在MDS和AML中至关重要，特别是在老年人中，因为由于治疗的毒性，这些疾病是不可治愈的。对患者进行CHIP检测是相对简单的，但是，我们不太了解哪些患者会发展为血癌。这一重要知识是我们对CHIP理解的一个很大差距，因为我们无法为受影响的患者提供适当的进一步信息。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作出反应（称为癌症免疫学）。癌细胞通常会发展出隐藏自己的方法来帮助它们生长。在过去的几年里，已经开发出了新的治疗方法，可以帮助免疫系统看到并摧毁癌细胞，或者创造出专门针对癌细胞的人工修饰的免疫细胞。针对癌细胞（特别是“T细胞”）的有效免疫反应是身体对抗癌症发展的最重要防御。有趣的是，针对CHIP/AML相关突变的T细胞应答已经被发现，然而，免疫系统在帮助控制CHIP及其向MDS/AML的进展中的作用尚不清楚。我们认为，对CHIP细胞的主动免疫可能会保护患者免于发生MDS/AML。因此，该项目的目标是详细了解免疫细胞以及它们如何在CHIP患者中工作。我们将研究CHIP特异性T细胞应答是否可以被识别，以及这些应答是否可以预测从CHIP到MDS/AML的进展。这个项目得益于获得一个独特的资源：英国老龄化纵向研究（艾尔莎）。艾尔莎是一项长期的老龄化研究（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，它完全适合研究CHIP及其随时间的进展/并发症。我们将对这些样本进行突变筛查，以识别CHIP患者，并评估CHIP如何随时间推移而进展。与艾尔莎，将与然后收集新的血液样本，从特定的个人与CHIP的免疫细胞进行更详细的分析。使用这些样本和世界一流的专业知识，在癌症免疫学的主办机构，我们将看看在CHIP免疫系统中的不同细胞的范围。特别是，我们将评估T细胞的类型和功能，以及它们如何随着CHIP进展而变化。我们还将研究血液中可能被CHIP改变的其他类型的免疫细胞。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物分离出携带CHIP突变的血细胞，将其与正常细胞进行比较。鉴于MDS/AML在老年人中的预后不良，本研究的长期目标是提高对CHIP生物学及其向MDS/AML进展的理解，使该领域朝着旨在改变血癌和其他CHIP相关健康问题发展风险的战略发展。

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.