Oesophageal adenocarcinoma (OAC) is a dismal prognosis cancer, whose incidence continues to increase year on year. Recent approvals by the FDA and EMA/HPRA allow for the use of novel immune-based therapies, including anti-PD-1 targeting agents in advanced OAC patients. While immune checkpoint inhibitors (ICIs) have revolutionised the field of cancer immunotherapy, engaged public interest and offered the possibility of cure for some patients, overall the response rates to ICIs remains poor, estimated to be from 13-29% across all cancers. Current clinical trials are focusing on combining different ICIs, or combining with chemotherapy/radiotherapy and assessing treatment scheduling, but few are currently targeting immune evasion strategies in combination with ICIs. This is a critical feature which is likely responsible for the poor response rates to ICIs across multiple cancer types and therefore future approaches should aim to counteract immunosuppressive pathways along with immune stimulatory therapies, such as ICIs.
This project aims to target an emerging evasion strategy used by solid tumours, which is the Siglec-sialic acid pathway. This pathway is dysregulated in tumours, with an overexpression reported in many solid tumours and is involved in the majority of cancer hallmarks, most notably immune evasion. Specific Siglec receptors are involved in T cell suppression including Siglec-7, -9 and -10, which will be the focus of this study. This project will examine sialylation and the expression of Siglec ligands on both OAC tumour cells and mesenchymal stromal cells under different biologically and clinically relevant conditions, reflective of the tumour microenvironment and cancer treatments. This study will also assess how T cells are suppressed through the Siglec-sialic acid pathways and how targeting this pathway could enhance T cell function. Lastly, we will investigate how dual targeting of ICIs and sialylation could enhance T cell function and ultimately improve outcomes for patients who receive ICIs.