'T cell versus T cell': A Study of the Cellular Immune Response in Cutaneous T cell Lymphoma (CTCL)
“T 细胞与 T 细胞”:皮肤 T 细胞淋巴瘤 (CTCL) 细胞免疫反应的研究
基本信息
- 批准号:MR/M019055/1
- 负责人:
- 金额:$ 27.01万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Fellowship
- 财政年份:2015
- 资助国家:英国
- 起止时间:2015 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Cutaneous T cell lymphomas (CTCL) are a group of malignant disorders derived from T lymphocytes, a type of white cell within our immune system. These malignant T cells settle mainly within the skin and cause severe complications. The rate at which the disease progresses within individual patients is variable but no genetic or phenotypic abnormalities of the tumour cell have been identified which determine disease progression. An alternative suggestion is that it is the patients' immune response to the tumour which regulates the aggressiveness of the disease. There is currently a great deal of interest in how our immune system may act to prevent or control cancer. Indeed, many patients with diseases such as lung cancer are now achieving long term remission after injection of molecules called antibodies that boost the strength of the immune system. Interestingly, these drugs are believed to act by increasing the activity of T cells - the very cell that is the cause of cancer in patients with CTCL. Evidence shows there is a cancer-specific immune response in patients with CTCL and in this fellowship we propose to investigate this in detail, in order to guide the introduction of new immune-based therapies. One fascinating aspect of the proposal is that we will examine how normal T cells are potentially able to control growth of malignant T cells. This will provide very novel information about the potential role of immune-modulatory therapy in patients with CTCL, which will be applicable to the treatment of cancer in general.In order to carry out this work we will recruit patients from one of the largest CTCL clinical units in Europe, and blood and skin biopsies will be taken at different stages of disease. Malignant and reactive T cells will be isolated and examined by multi-parameter flow cytometry, including a complete analysis of co-stimulatory molecule expression. We will use antibody probes to determine the pattern of expression, on both malignant and normal T cells, of the molecules that can suppress normal immune function. One exciting aspect here is that we will have access to a new technology, CtTOF, which will allow us to determine the presence of up to 34 proteins on the surface of cells at the same time. We will also try to find molecules within the malignant T cells that act as the targets for the immune response. We will focus on cancer testis antigens (CTAg), a remarkable family of proteins that normally only expressed in germ cells such as testis or ovary, but which are also expressed in many cancers. Using reagents called tetramers we will investigate the presence of CTAg-reactive T cells and assess why they are not effective in patients with progressive disease. Finally we will culture healthy T cells isolated from within CTCL biopsies with the CTCL cancer cells themselves, to see if they can recognise and kill the tumour cells. We will then use investigate how we can block inhibitory signalling molecules to investigate how we can strengthen killing of the cancer.We believe that we are strongly placed to perform this work as we bring together one of the largest and most academically active CTCL clinical units within the UK together with a very strong research team within tumour immunology. We anticipate that the results will contribute to a substantial increase in understanding of the mechanisms of immune evasion by CTCL. This research programme will have direct relevance to the study of tumour immunology both within CTCL and in relation to other forms of cancer. The beneficiaries of the work will therefore include academics working within tumour immunology and a wide range of cancer physicians. Most importantly, we believe that it can be used to guide the introduction of immune-stimulatory antibody therapy through a personalised approach in patients with CTCL.
皮肤T细胞淋巴瘤(CTCL)是一组源自T淋巴细胞的恶性疾病,T淋巴细胞是我们免疫系统中的一种白色细胞。这些恶性T细胞主要定居在皮肤内,并导致严重的并发症。疾病在个体患者中进展的速率是可变的,但尚未鉴定出决定疾病进展的肿瘤细胞的遗传或表型异常。另一种说法是,患者对肿瘤的免疫反应调节了疾病的侵袭性。目前,人们对我们的免疫系统如何预防或控制癌症非常感兴趣。事实上,许多患有肺癌等疾病的患者在注射称为抗体的分子后,现在正在实现长期缓解,这些分子可以增强免疫系统的强度。有趣的是,这些药物被认为是通过增加T细胞的活性来发挥作用的,T细胞是CTCL患者癌症的原因。有证据表明,CTCL患者存在癌症特异性免疫应答,在本研究中,我们建议详细研究这一点,以指导新的免疫疗法的引入。该提案的一个有趣的方面是,我们将研究正常T细胞如何能够控制恶性T细胞的生长。这将为CTCL患者的免疫调节治疗的潜在作用提供非常新颖的信息,这将适用于一般癌症的治疗。为了开展这项工作,我们将从欧洲最大的CTCL临床单位之一招募患者,并在疾病的不同阶段进行血液和皮肤活检。将分离恶性和反应性T细胞,并通过多参数流式细胞术进行检查,包括共刺激分子表达的完整分析。我们将使用抗体探针来确定恶性和正常T细胞上能够抑制正常免疫功能的分子的表达模式。一个令人兴奋的方面是,我们将获得一种新技术,CtTOF,它将使我们能够同时确定细胞表面上多达34种蛋白质的存在。我们还将尝试在恶性T细胞内寻找充当免疫反应靶点的分子。我们将重点关注癌症睾丸抗原(CTAg),这是一个显着的蛋白质家族,通常只在生殖细胞如睾丸或卵巢中表达,但也在许多癌症中表达。使用称为四聚体的试剂,我们将研究CTAg反应性T细胞的存在,并评估为什么它们在进行性疾病患者中无效。最后,我们将从CTCL活检组织中分离的健康T细胞与CTCL癌细胞本身一起培养,看看它们是否可以识别并杀死肿瘤细胞。我们相信我们有能力完成这项工作,因为我们将英国最大和最活跃的CTCL临床单位之一与肿瘤免疫学领域非常强大的研究团队结合在一起。我们预计,这些结果将有助于大量增加对CTCL免疫逃避机制的理解。该研究计划将直接关系到CTCL内的肿瘤免疫学研究以及与其他形式的癌症的关系。因此,这项工作的受益者将包括在肿瘤免疫学领域工作的学者和广泛的癌症医生。最重要的是,我们认为它可以用于指导通过个性化方法在CTCL患者中引入免疫刺激抗体治疗。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
'T-cell versus T-cell': Tumour infiltrating lymphocytes in mycosis fungoides show a remarkably homogeneous exhaustion profile across a heterogeneous patient population
“T 细胞与 T 细胞”:蕈样肉芽肿中的肿瘤浸润淋巴细胞在异质患者群体中表现出非常均匀的耗竭特征
- DOI:10.1016/j.ejca.2018.07.172
- 发表时间:2018
- 期刊:
- 影响因子:8.4
- 作者:Murray D
- 通讯作者:Murray D
The tumour phenotype of mycosis fungoides clusters into three heterogeneous surface expression profiles
蕈样肉芽肿的肿瘤表型分为三种异质表面表达谱
- DOI:10.1016/j.ejca.2018.07.173
- 发表时间:2018
- 期刊:
- 影响因子:8.4
- 作者:Murray D
- 通讯作者:Murray D
Single-cell RNA sequencing with TCR repertoire profiling of mycosis fungoides
单细胞 RNA 测序及蕈样肉芽肿的 TCR 谱分析
- DOI:10.1016/s0959-8049(19)30528-3
- 发表时间:2019
- 期刊:
- 影响因子:8.4
- 作者:Murray D
- 通讯作者:Murray D
Study of The Immune Microenvironment in Mycosis Fungoides
蕈样肉芽肿免疫微环境的研究
- DOI:
- 发表时间:2019
- 期刊:
- 影响因子:0
- 作者:Murray D
- 通讯作者:Murray D
T Cell Versus T Cell; A Study of the Immune Checkpoint Landscape in Cutaneous T Cell Lymphoma.
T 细胞与 T 细胞;
- DOI:
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Murray D
- 通讯作者:Murray D
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Duncan Murray其他文献
Exploring business students’ views of the use of generative AI in assignment writing
探索商学院学生对在作业写作中使用生成式人工智能的看法
- DOI:
10.14742/apubs.2023.662 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Duncan Murray;Karen Williams - 通讯作者:
Karen Williams
Expectancy Violation Exposes the Hidden Victims of Sexual Harassment
违反预期暴露了性骚扰的隐藏受害者
- DOI:
10.33423/jop.v22i2.5345 - 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Michelle Zacharko;Duncan Murray - 通讯作者:
Duncan Murray
National Emergency Department Overcrowding Study tool is not useful in an Australian emergency department
国家急诊科过度拥挤研究工具在澳大利亚急诊科没有用
- DOI:
10.1111/j.1742-6723.2006.00854.x - 发表时间:
2006 - 期刊:
- 影响因子:2.3
- 作者:
K. Raj;Kylie Baker;S. Brierley;Duncan Murray - 通讯作者:
Duncan Murray
P-167 - CD8 positive Sézary syndrome: two cases
P-167 - CD8 阳性塞扎里综合征:两例
- DOI:
10.1016/j.ejca.2023.113055 - 发表时间:
2023-09-01 - 期刊:
- 影响因子:7.100
- 作者:
Elizabeth Peterknecht;Kevin Molloy;Duncan Murray;Farida Shah;Bethanie Rooke;David Burns;Ye Lin Hock;Julia Scarisbrick - 通讯作者:
Julia Scarisbrick
Phase II trial of atezolizumab (Anti-PD-L1) in the treatment of relapsed/refractory IIB/IVB mycosis fungoides/Sézary syndrome patients after previous systemic treatment. EORTC-1652-CLTG “PARCT”
阿特珠单抗(抗程序性死亡配体1)用于既往接受过全身治疗的复发/难治性IIB/IVB蕈样肉芽肿/赛塞利综合征患者的II期试验。欧洲癌症研究与治疗组织 - 1652 - 皮肤淋巴瘤任务组“PARCT”
- DOI:
10.1016/j.ejca.2025.115484 - 发表时间:
2025-06-03 - 期刊:
- 影响因子:7.100
- 作者:
Rudolf Stadler;Gabriele Roccuzzo;Pablo Ortiz-Romero;Martine Bagot;Pietro Quaglino;Emmanuella Guenova;Constanze Jonak;Evangelia Papadavid;René Stranzenbach;Sandrine Marreaud;Jammbe Musoro;Jose Casas-Martin;Duncan Murray;Samantha Drennan;Jimmy Van Hear;Paul Moss;Delphine Sartori;Maxime Battistella;Rein Willemze;Julia Scarisbrick;Robert Knobler - 通讯作者:
Robert Knobler
Duncan Murray的其他文献
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