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

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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.