Characterising myeloid cells in chromosomally unstable cancers
Primary Supervisor: Dr Eileen Parkes
Second Supervisors: Dr Bruno Beernaert and Professor Eric O'Neill
Project Overview
Previously we identified that the central immune cGAS-STING pathway is chronically stimulated in chromosomally unstable cancers. Mis-segregated chromosomes as a result of CIN are sequestered in micronuclei to enable cell cycle progression. The nucleic acid sensor cyclic cGMP-AMP synthase (cGAS) tightly binds to micronuclei (cGAS+ve micronuclei), producing the second messenger 2’3’cGAMP which activates the Stimulator of Interferon Genes (STING). The cGAS-STING pathway is a central immune hub which is critical for effective anti-tumour immune responses. However, in CIN-high tumours, the cGAS-STING pathway is chronically stimulated – a paradox which the Parkes lab has studied, identifying cGAS-driven CXCL8 (IL8) as a critical orchestrator of the myeloid-enriched microenvironment in CIN-high OGC. This results in a macrophage and tumour-associated neutrophil infiltrate with subsequent immunosuppression. Patients with CIN-high OGC experience the poorest clinical outcomes. Despite this, no therapeutic approaches are currently available that target the immunosuppressive role of myeloid cells in CIN-high tumours. Understanding the unique features of tumour-resident and circulating neutrophils in CIN-high OGC will enable the development of effective treatment strategies. The aims of this project will (1) Characterise tumoral and circulating myeloid populations in patients with CIN-high OGC, using an existing matched tissue-blood pipeline. (2) In vivo modelling of CIN-high OGC and characterising of myeloid microenvironment and (3) explore therapeutic strategies which remodel the CIN-high microenvironment, permitting immune response.
Training Opportunities
The student will gain hands-on experience in cutting-edge laboratory techniques including multiplex immunofluorescence, high-dimensional flow cytometry, spatial tissue analysis, and RNA sequencing, supported by experts at the Kennedy Institute, NDORMS, and Oncology. The project also provides training in data analysis, interpretation, and integration of multi-modal datasets, supported by bioinformatics collaborators. Exposure to translational pipelines, such as sample collection through the INTEGRATOR platform, will enhance the student’s understanding of how laboratory findings can be linked to clinical outcomes.
References
Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis. Bruno Beernaert, Rose L Jady-Clark, Parin Shah, Erik Ramon-Gil, Nora M Lawson, …, Ester M Hammond, Kadir C Akdemir, Jack Leslie, Benjamin Izar, Eileen E Parkes. bioRxiv 2025.05.06.652454;