Investigating cell-matrix networks as determinants of tumour immune response in oropharyngeal squamous cell carcinoma

背景：头颈部鳞状细胞癌（HNSCC）是一种发生在喉咙内壁的癌症，可发生在口腔、咽部、喉部和下咽（食道顶部）。罹患HNSCC的人数每年都在增加，30%到70%的人因此死亡，这取决于他们的癌症在喉咙的位置。治疗方法包括放疗、化疗和/或手术，幸存者可能会出现说话、吞咽和呼吸问题。尽管治疗方法有所进步，但结果并没有改善。针对免疫系统的新药物（免疫疗法）已用于无法治愈的HNSCC患者，可将总生存率提高15%。然而，这些药物有明显的副作用，我们不知道如何提前告诉哪些病人会得到帮助。肿瘤是由癌细胞、免疫细胞和成纤维细胞的混合物组成的，成纤维细胞通常有助于伤口愈合。细胞外基质（ECM）是由成纤维细胞产生的蛋白质混合物，它将细胞聚集在一起并帮助它们交流。免疫细胞可以帮助我们对抗癌症，并影响治疗的效果。要做到这一点，正确类型的免疫细胞必须以足够数量到达肿瘤的正确位置。即使在相同类型的癌症中，这也会有很大差异。一般来说，拥有更多免疫细胞的肿瘤对治疗有更好的反应和更好的结果。然而，我们不知道是什么控制着免疫细胞如何进入肿瘤。成纤维细胞在HNSCC中大量存在。有不同类型的成纤维细胞，其中一些是异常的，可以帮助癌细胞存活。肿瘤中的ECM也是异常的，可以变得非常僵硬。有一些证据表明，在其他癌症中，成纤维细胞和ECM可以阻止免疫细胞有效工作，并为它们进入肿瘤制造障碍。我们想在HNSCC中研究这一点。目的和目的本项目旨在发现成纤维细胞和细胞外基质是否改变了HNSCC中免疫细胞的行为。我们将通过使用患者的样本来做到这一点。手术切除HNSCCs的患者会被要求允许我们使用不需要治疗的癌症小块。我们将分析这些癌症，列出HNSCC中确切的细胞类型，并观察这些细胞制造什么蛋白质。我们将把它与健康组织中的细胞类型进行比较。我们将使用计算机分析来找出细胞和蛋白质是如何相互作用来改变免疫细胞并使癌症存活下来的。然后，我们将在显微镜下观察样本，看看细胞和基质蛋白之间的关系，看看我们关于它们如何相互作用的想法是否正确——有点像绘制肿瘤的路线图。最后，我们将使用“外植体”；肿瘤的活体切片，来改变这些细胞的行为，看看这是否会改变肿瘤内的免疫细胞。潜在的应用和益处这项工作将帮助我们了解HSNCC中不同的细胞类型如何影响免疫系统对肿瘤的反应。了解癌症细胞之间的相互作用将帮助我们理解为什么针对免疫系统的疗法在HNSCC中不起作用，如何选择这些疗法可能有效的患者，并为那些不会受益的患者提出新的治疗方案。

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a cancer of the lining of the throat, which can occur in the mouth, pharynx (throat), larynx (voicebox) and hypopharynx (top part of the gullet). The number of people developing HNSCC is increasing each year, and between 30 and 70% die as a result, depending on where in the throat their cancer is. Treatment is with radiotherapy, chemotherapy and/or surgery, and can leave survivors with problems speaking, swallowing and breathing. Despite advances in treatments, outcomes haven't improved. New medications that target the immune system (immunotherapies) have been used in patients with incurable HNSCC and can improve overall survival by up to 15%. However, these medications have significant side effects, and we don't know how to tell in advance which patients will be helped.Tumours are made of a mixture of cancer cells, immune cells, and cells called fibroblasts, which usually help wounds heal. The extracellular matrix (ECM) is a mixture of proteins made by fibroblasts, which holds the cells together and helps them communicate. Immune cells can help us fight cancer, and affect how well treatments work. For this to happen, the right types of immune cells have to get to the right place in the tumour in sufficient numbers. This can vary a lot even within the same types of cancer. In general, tumours with more immune cells have better responses to treatments and better outcomes. However, we don't know what controls how immune cells get into tumours. Fibroblasts are found in large numbers in HNSCC. There are different types of fibroblasts, some of which are abnormal and can help cancer cells survive. The ECM in tumours is also abnormal and can become very stiff. There is some evidence in other cancers that fibroblasts and the ECM can stop immune cells from working effectively and create barriers to them getting into tumours. We want to investigate this in HNSCC.Aims and ObjectivesThis project aims to find out if fibroblasts and the extracellular matrix alter how immune cells behave in HNSCC. We will do this by using samples from patients. Patients having surgery to remove HNSCCs will be asked permission for us to use small pieces of their cancer that are not needed for their treatment. We will analyse the cancers to make a list of exactly what cell types there are in HNSCC, and to see what proteins these cells are making. We will compare this with the cell types in healthy tissue. We will use computer analysis to work out how the cells and proteins are interacting to change the immune cells and allow the cancer to survive. We will then look at the samples under a microscope, to see where cells and matrix proteins are in relation to one another, and to see if our ideas about how they are interacting are right - a bit like creating a road map of the tumour. Finally, we will use 'explants'; living sections of tumours, to change how these cells are behaving and to see if this alters immune cells within the tumour. Potential applications and benefitsThis work will help us understand how different cell types in HSNCC affect how the immune system responds to tumours. Understanding the interactions between cells within cancers will help us understand why therapies that target the immune system haven't worked well in HNSCC, how to choose patients that these therapies might work well for, and come up with new treatment options for patients that they won't benefit.