Crosstalk Between Tumour and Draining Lymph Nodes and its Impact on Triple-Negative Breast Cancer

人体包含约500个豆状免疫器官，即所谓的淋巴结，作为淋巴系统的一部分。当淋巴结感觉到外来的东西，如癌细胞，它会发生结构变化，发出信号，指示新免疫细胞产生的位置。这些斑块被称为生发中心。来自这些生殖中心的一些免疫细胞，称为浆细胞，将产生称为免疫球蛋白的标记物，它们将用于标记外来分子。这种标记策略允许杀手免疫细胞轻松追踪和摧毁癌细胞。另一种类型的免疫细胞，记忆B细胞，产生于生发中心，帮助免疫系统记住哪些分子是外来的。因此，如果将来我们的免疫系统再次遇到这些外来分子，它可以立即采取行动，产生标记，并更快地消灭入侵者。我们发现，淋巴结中出现生发中心可以帮助识别乳腺癌患者，这些患者总体上会活得更长。我们现在知道，这些淋巴结变化携带着重要的信息，特别是在具有非常侵袭性癌症的乳腺癌患者亚组中，并且在初步诊断后不久在远处器官中发生继发性癌症。我们未发表的数据表明，血浆和记忆B细胞可能参与肿瘤和淋巴结。与此同时，我们已经开始在实验室中使用小鼠模型，我们发现肿瘤生长导致生发中心形成。这使我们有机会剖析肿瘤生长如何依赖于淋巴结中生发中心的出现，以及是否有一定的事件顺序来减缓这些高危患者的肿瘤生长。我们是一个由临床医生，湿实验室科学家和计算科学家组成的多学科团队，长期合作。在这项提案中，我们将利用我们在转化研究中结合生物学，组织病理学，成像和计算机编程的专业知识。我们将使用多种方法的组合，包括称为“空间转录组学”的新技术，这将帮助我们了解哪些分子存在于这些生殖中心和肿瘤中。通过使用乳腺癌的临床前小鼠模型，我们将询问记忆B细胞和浆细胞在癌症中的直接作用。通过扩展小鼠模型并利用手术前接受化疗的患者的癌症和淋巴结组织，我们将能够评估我们发现的重要性并测试对化疗的反应。总之，我们的工作不仅有助于首次了解淋巴结中的生殖中心及其在肿瘤微环境中的相关免疫反应，而且还可能对预测谁可能从当前的标准治疗中受益以及将来从目前临床上出现的免疫治疗中受益产生重大影响。

The human body contains ~500 bean-shaped immune organs, so-called lymph nodes, as part of the lymphatic system. When lymph nodes sense something foreign, such as cancer cells, it undergoes structural changes, signalling a location where new immune cells are produced. These patches are called germinal centres. Some immune cells derived from these germinal centres, called plasma cells, will produce markers called immunoglobulins, which they will use to label foreign molecules. This labelling tactic allows killer immune cells to easily track down and destroy cancer cells. Another type of immune cell, memory B cells, produced in the germinal centres helps the immune system to remember which molecules are foreign. So, if in future our immune system encounters these foreign molecules again, it can then act immediately to produce labels and eliminate the invader much more rapidly.We found that the appearance of germinal centres in lymph nodes can help to identify breast cancer patients who will overall live longer. We now know that these lymph node changes carry important information especially in a subgroup of breast cancer patients with very aggressive cancers and who develop secondary cancer in distant organs soon after initial diagnosis. Our unpublished data indicate that both plasma and memory B cells might be involved at the tumour and in lymph nodes. In parallel, we have started work with mouse models in our laboratories where we found that tumour growth causes germinal center formation. This gives us now the opportunity to dissect how the tumour growth is dependent on the appearance of germinal centres in lymph nodes and whether there is a certain order of events necessary to slow down tumour growth in these high-risk patients. We are a multi-disciplinary team of clinicians, wet-laboratory scientists and computational scientists with long-standing collaboration. In this proposal, we will leverage our expertise in combing biology, histopathology, imaging and computer programming in translational research. We will use a combination of approaches, including novel technologies called "spatial transcriptomics" which will help us to understand which molecules are present in these germinal centres and at the tumour. By using pre-clinical mouse models representative of breast cancers we will interrogate the direct role of memory B cells and plasma cells in cancer. By expanding on mouse models and utilising tissue from cancer and lymph nodes from patients who received chemotherapy before surgery, we will be able to assess the importance of our findings and test response to chemotherapy.In summary, our work will not only contribute to understanding for the first time the role of germinal centers in lymph nodes and their related immune response in the tumour microenvironment, but also may have a major impact in predicting who might benefit from current standard-of-care therapies, and in future from the immune therapies that are currently emerging in the clinic.