Immunotherapeutic opportunities in oesophageal adenocarcinoma

Evans, Richard PT (2024). Immunotherapeutic opportunities in oesophageal adenocarcinoma. University of Birmingham. Ph.D.

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Abstract

Integration of immunotherapy into the treatment pathways for many solid cancers has led to important improvements in survival outcomes. Until recently there was no evidence to confirm that immunotherapy could improve survival over and above current gold standards in treatment for patients with potentially curative oesophageal cancer. Checkmate 577 has demonstrated that adjuvant PD-1 inhibition improves disease free survival for patients who have undergone neoadjuvant chemoradiotherapy and oesophagectomy. Oesophageal adenocarcinoma (OAC) is potentially susceptible to immunotherapy however little is known about the tumour microenvironment (TME). This thesis explores the immunophenotypic landscape of oesophageal adenocarcinoma to identify new mechanisms for immunotherapy.

A combination of proteomic and transcriptomic studies have identified that the OAC TME is dominated by immune and stromal populations. T cells are the majority immune population, and a range of effector and regulatory subsets were identified. OAC is broadly immunogenic and CD39+ T cells, generally regarded as correlates of a tumour-specific cytotoxic cellular response, are observed in both CD4+ and CD8+ T cell subsets. T cells within the TME often express an exhausted phenotype with high levels of checkpoint expression (PD-1, Tigit, TIM-3, LAG-3). A highly proliferative population of T cells has been identified that exhibit features of tumour specificity but in addition feature similar rates of checkpoint expression. Neoadjuvant chemotherapy decreases immunosuppressive Tregs and can potentially decrease exhaustion in effector phenotypes.

These findings have significant implications in the development of novel immunotherapy which is already starting to show promise in improving survival for this challenging cancer.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):