The role of tumour immunology and the microbiome in the response to neoadjuvant chemotherapy in locally advanced colon cancer

Colorectal cancer (CRC) is the third most common malignancy diagnosed globally and second most common cause of cancer-related death. Standard treatment for locally advanced operable colon cancer (CC) is surgery +/- adjuvant chemotherapy. Immune cells in the tumour microenvironment (TME) and overall host tumour response play a crucial role in cancer progression and response to treatment. The gut microbiome is acknowledged to play a potential role in cancer initiation, development, and response to treatment. The effect of neoadjuvant chemotherapy (NAC) on immune cells in the TME, regional lymph nodes (LNs), and the gut microbiome has never been investigated in CC. The Fluoropyrimidine, Oxaliplatin and Targeted-Receptor pre-Operative Therapy (FOxTROT) trial demonstrated a reduction in risk of recurrence in locally advanced CC with 6 weeks of NAC. This thesis investigated the effect of NAC on local and regional immunity, the tumour microbiome, and explored prognostic and predictive biomarkers in FOxTROT.
Pathologist assessment and artificial intelligence were used to investigate local immunity and regional LNs. Composition of immune cells and LN size and number differed significantly by treatment arm, mismatch repair status, and stage. Several known prognostic markers remained prognostic following treatment with NAC, with other novel prognostic biomarkers identified, whilst multiplex immunofluorescence identified M1 macrophages as a potential predictive marker of response.
The tumour microbiome of a subset of cases was successfully analysed using low-coverage whole genome sequencing with differences in microbial composition by response to NAC identified, but no difference in alpha diversity or microbial abundance found between treatment arms. The findings show the impact of NAC on local immunity, regional LNs and the microbiome for the first time in CC. Validation of prognostic markers in specimens following NAC is of clinical relevance with increasing use of NAC in
CC. The results suggest potential predictive biomarkers of response that require validation.