The interplay between the gut metabolome and immune system and their role on the efficacy of neoadjuvant chemotherapy in early breast cancer

Lambie, Georgia (2025) The interplay between the gut metabolome and immune system and their role on the efficacy of neoadjuvant chemotherapy in early breast cancer. MSc(R) thesis, University of Glasgow.

Abstract

Promising results have identified the gut microbiome and immune system as important modulators of response to cancer therapies. This provided a rationale for the current study to explore their combined roles on influencing response to neoadjuvant chemotherapy (NACT) in early-breast cancer patients enrolled in the NEO-MICROBE BREAST clinical study. This study aimed to characterise the composition of metabolites within the gut by conducting LCMS analysis on stool samples from cancer patients. A second aim was to start the process of immunophenotyping peripheral blood mononuclear cells through optimisation of a novel 10-colour flow cytometry panel.

Untargeted and targeted metabolomics data analysis of the stool samples profiled the gut metabolic environment of cancer patients and healthy volunteers highlighting several metabolites indicative of NACT response: elucidating alpha-ketoglutarate (aKG) and citrate as potential biomarkers for achievement of pathological complete response, associating guanine and uridine with non-response to NACT and uridine-5’-monophosphate (UMP) potentially linked to cancer status. In combination with metabolomic analysis of blood samples from the same cohort; glutamate demonstrated a correlation between higher stool- and blood- derived levels in TNBC patients, demonstrating potential direct involvement of glutamate in the response to NACT.

A 10-colour panel was generated and optimised via flow cytometry analysis of PBMCs from healthy blood donors and its ability to successfully identify T cell subsets associated with breast cancer was validated. Upon further validation to allow for optimal marker detection, this panel provides the foundation for future PBMC immunophenotyping of this cohort. Overall, this study strengthens the evidence that NACT efficacy may be influenced by the involvement of gut-derived metabolites and systemic modulation; and highlights the importance of the immune-profiling of breast cancer to allow for a comprehensive approach to improve NACT response via personalised treatment.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Subjects: Q Science > QR Microbiology; Q Science > QR Microbiology > QR180 Immunology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: MacPherson, Professor Iain and Milling, Professor Simon
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85425
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 03 Sep 2025 09:04
• Last Modified: 03 Sep 2025 09:07
• Thesis DOI: 10.5525/gla.thesis.85425
• URI: https://theses.gla.ac.uk/id/eprint/85425