The regulation of tumour cell cytolysis by cancer associated fibroblasts

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Context of researchThe tumour microenvironment includes a diverse number of cell types including immune cells, fibroblasts, and endothelial cells. Investigating the association between cytotoxic T lymphocytes (CTLs) and cancer associated fibroblasts (CAFs) could provide insights into the crosstalk and impact of CTLs and CAFs on tumour progression and also opens new areas for therapeutic intervention. CTLs are immune cells that can kill cancer cells. However, recruitment and activation of CTLs is often suppressed in the tumour. CAFs shape the extracellular matrix and can secrete immune-modulatory as well as tumour promoting/restricting cytokines. Further research is needed to better understand the impact of CAFs on CTLs ability to kill tumour cells. Aims and ObjectivesThe project has 2 major aims. Aim 1 focuses on CAFs and asks how different CAFs interact with tumour cells and immune cells, particularly CTLs. We will characterise CAFs (particularly those associated with breast and colorectal cancer) and investigate their ability to support cancer cell proliferation in 2D and 3D co-culture assays. In parallel, we will assess the immune-suppressive function of CAFs, e.g. the impact of the CAF secretome on CTL proliferation, migration and the cytolytic activity of CTLs. The objective is to then combine CAFs, tumour cells and CTLs into a 3D co-culture model. Aim 2 will focus on the activity of novel bispecific T-cell engagers (BiTEs). The BiTEs will bind both T-cells and receptors such as EGFR or HER2 on tumour cells. We will compare CTL-induced killing of tumour cells by endogenous CTLs and BiTE-directed CTLs. The project will further address whether expression of varying levels of EGFR/HER2 on cancer cells has an impact on the activity profile of the BiTEs. To better understand the role of CAFs on therapy response, we will bring aim 1 and 2 together, and investigate the impact of CAFs on CTL and BiTE-directed CTL induced tumour cell cytolysis in the co-culture system. potential application and benefitsCAFs are implicit in many solid tumours and are therefore an attractive target for cancer therapy. A clear understanding of their function and interaction with other cells would allow for better drug design. Furthermore, studying the mechanism of function of a bispecific molecule within the CAF/CTL environment will aid development of future immunotherapies. Relevance to the research councilThis is PhD project is within the GW4-BioMed-2 DTP. It is within the "Infection, immunity, antimicrobial resistance and repair" theme. The proposed project is aligned with the MRC's strategy to invest in research addressing biological complexity in real life and is relevant to the MRC's health focus themes of 'precision medicine' and 'advanced therapies'. Furthermore, it addresses core skill areas outlined by the GW4-BioMed-2 DTP including quantitative and interdisciplinary skills.