Understanding how to effectively reprogram the immunosuppressive tumour microenvironment to improve tumour responses while limiting toxicity

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With the advent of immune checkpoint blockade as standard of care in many cancers, such as oesophageal adenocarcinoma (OAC), there is now a pressing need to identify new combination strategies for the very high proportion of immune checkpoint blockade-resistant or non-responding diseases. OAC is a solid cancer of unmet need, on course to impact increasing numbers of people and yet poorly characterised in terms of tumour microenvironment. OAC is a disease of high chromosomal instability, a critical feature that has downstream impacts on immune responses.

Work in the Parkes lab has identified a specific inflammation phenotype in chromosomally unstable, cGAS-STING pathway active cancers. Using single cell data and digital pathology approaches we previously characterised the myeloid infiltrate in chromosomally unstable cancers. CIN-high OAC has high expression of genes involved in organisation and remodelling of the extracellular matrix, which determines the structure of the tumour and induces a distinct fibroblast phenotype within the microenvironment. How this in turn affects the immune compartment of CIN-high OAC cancers remains to be characterised. In addition, the link between CIN-status, tumour microenvironment and response to immunotherapy has still to be explored.

In this project, the candidate will characterise the extracellular matrix and mechanical properties of the tumour and its microenvironment in chromosomal instability that subsequently impact the immune response. Aims (1) Profile fibroblast profile in CIN-high OAC using digital pathology and spatial transcriptomics (2) Develop 3D models of CIN-fibroblast interactions (3) Establish ex-vivo models of extracellular matrix recapitulating tumour microenvironment to interrogate interaction between tumour structure and fibroblast phenotype.

Training Opportunities

The student will be given training in immunology and molecular biology techniques including flow cytometry, 3D culturing of organoid models, primary tissue processing, cell sorting, cell and tissue mechanics, digital pathology analysis as well as bioinformatic training for single cell and spatial RNAseq analysis. Students will also have the opportunity to attend bioinformatics training to learn or advance their bioinformatic skills.