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

自20世纪70年代以来，英国黑色素瘤的发病率比任何其他癌症都增长得更快，2011年有13，348名受影响的患者。虽然近年来发病率的增加在60岁以上的人群中更大，但黑色素瘤在非常年轻的成年人中发生的比例很大。虽然大多数黑色素瘤患者，谢天谢地，通过手术治愈，直到最近，黑色素瘤已经扩散到其他器官的治疗一直很可怕。过去6年的进展是，即使是晚期黑色素瘤也已通过激活患者免疫反应的治疗方法成功治疗（显然是长期治疗）：有效地鼓励患者自身的免疫系统拒绝他们的癌症。尽管这些长期对策是开创性的，但要利用这些进展，还需要做很多工作。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进展（所谓的辅助治疗）的患者。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，他们的免疫细胞侵入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，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进展，并似乎与免疫反应的抑制有关。病理学家在显微镜下看到许多发炎的肿瘤有皮肤表面的溃疡，这与较差的生存有关。这种溃疡在吸烟者中更常见，在血液中维生素D水平较高的人中不太常见。在这项申请中，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做到这一点，这是该小组的专业知识。我们正在为利兹的一项研究招募人员，在这项研究中，患者提供血液样本，并允许我们从他们的肿瘤和储存在国民保健服务实验室的淋巴腺中提取样本。我们将使用实验室技术来研究这些肿瘤、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性。通过这样做，我们将能够研究炎症、溃疡、吸烟、维生素D和不同类型的肿瘤如何与不同的免疫活性模式相关联。如果我们能够确定是什么让一些患者产生免疫反应，癌症如何关闭免疫反应以及哪些因素影响这些过程，那么我们认为我们将能够开发出可用于早期疾病的低毒性治疗方法，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有害的炎症，如与吸烟和肥胖有关的炎症，会抑制对癌症的免疫反应，降低生存率和维生素D的作用。因此，我们将能够在诊断时更好地建议患者有关可能对其预后重要的因素，如果炎症确实在抑制对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治疗，如阿司匹林和其他非甾体抗炎药作为辅助治疗。 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（预测性生物标志物），以将药物治疗靶向那些受益最大的人。

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.