'T cell versus T cell': A Study of the Cellular Immune Response in Cutaneous T cell Lymphoma (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细胞。这些恶性T细胞主要停留在皮肤内，并引起严重的并发症。个别患者的疾病进展速度是可变的，但尚未发现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了一种叫做抗体的分子后，他们的病情得到了长期缓解，这种分子可以增强免疫系统的力量。有趣的是，这些药物被认为是通过增加T细胞的活性来起作用的，而T细胞正是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反应，在本研究中，我们建议对此进行详细研究，以指导新的免疫疗法的引入。这个提议的一个吸引人的方面是，我们将研究正常T细胞如何潜在地能够控制恶性T细胞的生长。这将为CTCL患者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。恶性和反应性T细胞将被分离并通过多参数流式细胞术检测，包括对共刺激分子表达的完整分析。我们将使用抗体探针来确定可以抑制正常免疫功能的分子在恶性和正常T细胞上的表达模式。一个令人兴奋的方面是，我们将获得一项新技术，ctof，这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细胞内寻找作为免疫反应目标的分子。我们将重点关注癌睾丸抗原（CTAg），这是一个非凡的蛋白家族，通常只在生殖细胞如睾丸或卵巢中表达，但在许多癌症中也表达。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，并评估它们对进行性疾病患者无效的原因。最后，我们将从CTCL活检中分离出的健康T细胞与CTCL癌细胞本身进行培养，看看它们是否能识别并杀死肿瘤细胞。然后我们将研究如何阻断抑制信号分子来研究如何加强对癌症的杀伤。我们相信，我们有很强的能力来完成这项工作，因为我们汇集了英国最大、学术上最活跃的CTCL临床单位之一，以及一个非常强大的肿瘤免疫学研究团队。我们预计这些结果将有助于大大增加对CTCL免疫逃避机制的理解。该研究项目将与CTCL和其他形式癌症的肿瘤免疫学研究直接相关。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，我们相信它可以用于指导CTCL患者通过个性化方法引入免疫刺激抗体治疗。

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.