Using tumour, peripheral blood and sentinel nodal transcriptomics to understand the interaction between melanomas and the host

自20世纪70年代S以来，英国黑色素瘤发病率的增长速度比其他任何癌症都要快，2011年有13,348名患者受到影响。虽然近年来黑色素瘤的发病率在60岁以上的人群中增加得更多，但黑色素瘤在非常年轻的成年人中发生的比例很高。谢天谢地，尽管大多数黑色素瘤患者都通过手术治愈了，但直到最近，已经扩散到其他器官的黑色素瘤的治疗一直很糟糕。过去6年的进展是，通过激活患者的免疫反应：有效地鼓励患者自身的免疫系统排斥他们的癌症，即使是晚期黑色素瘤也得到了成功的治疗(显然是长期的)。尽管这些长期应对措施是开创性的，但要利用这一进展，还有很多工作要做。有必要预测谁会有反应，为无反应者寻找药物，特别是在疾病早期识别需要并将受益于免疫治疗以防止病情恶化的患者(所谓的辅助治疗)。为了满足这些需求，需要更好地了解是什么决定了患者的免疫系统如何与肿瘤细胞相互作用。现有的研究表明，在一些患者中，他们的免疫细胞入侵肿瘤，并可能实际上摧毁它。然而，很明显，肿瘤细胞通常会感觉到这种攻击，并能够关闭这些免疫反应。我们有初步证据表明，有许多因素可以调节这一过程：全身和肿瘤中的一种有害炎症可能会促进肿瘤的发展，并似乎与免疫反应受到抑制有关。许多发炎的肿瘤在显微镜下可以看到病理学家看到的皮肤表面的溃烂，这与存活率较低有关。这种溃疡在吸烟者中更常见，在血液中维生素D水平较高的人中较少见。在这项应用中，我们寻求资金以更好地了解溃疡、炎症、吸烟和维生素D在生存中的作用以及肿瘤细胞和免疫系统之间的相互作用。该项目旨在使用遗传学的一种形式来实现这一点，这是该小组的专长。我们正在招募到利兹的一项研究，在该研究中，患者提供血液样本，并允许我们从他们的肿瘤和储存在NHS实验室的淋巴腺中提取样本。我们将使用实验室技术来观察这些肿瘤、血液样本和淋巴腺中的基因是如何表达的。然后，我们将使用基于计算机的测试(生物信息学)来估计这些数据中免疫系统不同部分的活动。在这样做的过程中，我们将能够研究炎症、溃疡、吸烟、维生素D和不同的肿瘤类型如何与不同的免疫活动模式相关联。如果我们因此能够确定是什么允许一些患者启动免疫反应，癌症是如何关闭这种免疫反应的，以及哪些因素影响了这些过程，那么我们将能够开发出可用于早期疾病的低毒治疗方法，并确定将从这些治疗中受益的患者。我们将了解是否有证据表明，与吸烟和肥胖相关的有害炎症会抑制癌症的免疫反应，降低存活率和维生素D的效果。因此，我们将能够在确诊时更好地向患者提供可能对其预后重要的因素的建议，如果炎症确实在抑制黑色素瘤的免疫反应中发挥作用，那么我们将探索常见的药物疗法，如阿司匹林和其他非类固醇抗炎药作为辅助疗法。在项目的最后阶段，我们将利用我们所学到的知识来设计测试(预测性生物标记物)，将药物治疗的目标对准那些受益最大的人。

UK melanoma incidence has increased more rapidly since the 1970's than any other cancer and in 2011 there were 13,348 affected patients. Although the increased incidence in recent years has been greater in people over the age of 60, melanoma occurs in a significant proportion in very young adults. Although the majority of melanoma patients, thankfully are cured by their surgery, until very recently indeed, the treatment for melanoma which has spread to other organs has been terrible. The progress in the last 6 years has been that even advanced melanoma has been successfully treated (apparently for the long term) with treatments that work by activating immune responses in the patient: effectively encouraging the patient's own immune system to reject their cancer. Although these long term responses have been ground breaking much needs to be done to capitalise on the progress. There is a need , to predict who will respond, to find drugs for the non-responders and especially to identify patients early in their disease who require, and will benefit from immunotherapy to prevent progression (so-called adjuvant treatment). In order to meet these needs, a better understanding of what determines how patients' immune systems interact with the tumour cells is needed. Existing research has shown that in some patients, their immune cells invade the tumour and may actually destroy it. However, it is clear that the tumour cells often then sense that attack and are able to turn off those immune responses. We have preliminary evidence that a number of factors can modulate this process: that a harmful sort of inflammation in the whole body and in the tumour may promote the progression of the tumour and appears to be associated with a suppression of immune responses. Many inflamed tumours have ulceration of the skin surface seen by the pathologist down the microscope, which is associated with poorer survival. This ulceration is more common in smokers and less common in people with higher levels of vitamin D in their blood. In this application we seek funding to better understand ulceration, the role of inflammation, smoking and vitamin D in survival and the interaction between tumour cells and the immune system. The project is designed to do this using a form of genetics, which is the expertise of the group. We are recruiting to a study in Leeds, in which patients give blood samples and allow us to take samples from their tumours and their lymph glands stored in NHS laboratories. We will use laboratory techniques to look at how the genes in those tumours, blood samples and lymph glands are expressed. We will then use computer based tests (bioinformatics) to estimate the activity of different parts of the immune system in those data. In so doing we will be able to study how inflammation, ulceration, smoking, vitamin D, and different tumour types associate with different patterns of immune activity. If we can thereby identify what allows some patients to mount an immune response, how the cancers turn off that immune response and what factors affect these processes, then we argue that we will be able to both develop low toxicity treatments which can be used in early disease and to identify patients who will benefit from those treatments. We will understand if there is evidence that harmful inflammation such as that associated with smoking and obesity suppresses immune responses to cancer and reduces survival and the effects of vitamin D. We will therefore be able to better advise patients at diagnosis about factors which may be important to their prognosis and if inflammation does play a role in suppressing immune responses to melanoma then we will explore common drug therapies such as aspirin and other non-steroidal anti-inflammatory drugs as adjuvant therapies. In the final period of the project we will use what we have learned to devise tests (predictive biomarkers) to target drug treatments to those who will benefit most.