Deciphering immune signalling changes and the influence of irradiation in SWI/SNF deficient cells

Our bodies are able to fight off infections by recognising the invading germs as 'different' from the rest of the cells in our bodies. This is done by the immune system. When cells become cancerous, the changes that they undergo can also lead to them becoming 'different' from the rest of the cells in our bodies, and recognised by the immune system. Immunotherapy can boost the ability of our immune system to impair cancer cell growth and survival. However, not all cancers respond to immunotherapy, and at the moment, it is not entirely clear why that is. In this proposal, we aim to investigate two factors that influence changes in immune responses in order to better understand why some cancers respond well to immunotherapy and others don't.
One factor that we will investigate is the SWI/SNF complex. This is a group of proteins that works together to modify the organisation of DNA in cells. This complex is frequently defective in cancer - roughly one in four cancers have impaired SWI/SNF. We know that SWI/SNF can influence response to immunotherapy, but we don't know how. Therefore, we will explore how SWI/SNF works to keep cells looking 'normal' to the immune system, and how this goes wrong when SWI/SNF is defective.
The second factor that we will investigate is irradiation. Treating cells with radiation leads to damaged DNA, which makes it difficult for cells to survive. This makes radiotherapy a good option for treating cancer in the clinic. Irradiating cells can also change the way they are recognised by the immune system, so they no longer look 'normal' and are eliminated, which is an additional strength of radiotherapy. However, just like with immunotherapy, the effect of radiotherapy on the ability of the immune system to work is variable, and it's not entirely clear why. Here, we will look at these changes in more detail in order to better understand the relationship between irradiating cells and the immune system. We also look at what happens when the cancer cells with SWI/SNF defects are irradiated.
Together, these studies will allow us to better understand the relationship between SWI/SNF defects, irradiation, and the immune system. This will help with understanding more about when and how to make better use of immunotherapy and radiotherapy with cancer patients.

The interplay between the cellular response to ionising radiation and immune signalling has important therapeutic consequences, but the responses are complex and not yet fully understood. We established that the SWI/SNF chromatin remodelling complex is important for both normal immune pathway signalling and radiation responses, but the mechanistic basis for these changes remains obscure. Irradiated cells also show changes in their immune signalling pathways. Moreover, in both irradiated cells and SWI/SNF deficient cells, there are alterations to the composition of the proteasome.

Here, we propose to investigate the mechanistic basis for altered immune signalling and proteasome composition in SWI/SNF deficient cells, and how this is influenced by irradiation. We will also investigate how altered proteasome composition impacts on proteasome activity, and how these changes influence the population of cell surface antigens (the immunopeptidome). Understanding these cellular pathways and their regulation by SWI/SNF and/or irradiation at a molecular level is important because SWI/SNF is defective in about 25% of human cancers, and radiotherapy is widely used in the clinic.

The results obtained will yield important insights into normal and tumour responses to irradiation, and provide a mechanistic framework for guiding new developments in immunotherapy and radiotherapy.