Immune and stromal tumour biology associated with neoadjuvant radiotherapy response in locally advanced rectal cancer
6 affiliations
- 1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Bearsden, UK
- 2Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
- 3Department of Oncology, Medical Sciences Division, University of Oxford, Old Road Campus Research Building, Oxford, UK
- 4Patrick G. Johnston Centre for Cancer Research, Queens University Belfast, Belfast, Northern Ireland UK
- 5Department of General Surgery, Queen Elizabeth University Hospital, Glasgow, UK
- 6Cancer Research UK Scotland Institute, Glasgow, UK
Abstract
Background: Response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC) is heterogeneous. The Neoadjuvant Rectal (NAR) score quantifies treatment response via tumour downstaging and nodal status and correlates with survival outcomes. This work set out to explore whether low NAR and high NAR tumours represent biologically distinct groups pre-treatment.
Methods: Transcriptome microarrays quantified RNA expression within pre-treatment biopsies from LARC patients in GSE87211 and S:CORT consortium Grampian datasets. A validation cohort from the Beatson West of Scotland Cancer Centre was analysed using multiplex immunofluorescence and H&E-derived tumour-stromal ratios.
Results: Seventeen MSigDB Hallmarks were enriched in high NAR tumours; ‘Epithelial-Mesenchymal Transition’ was notably enriched (padj < 0.001). Immune-related signatures were enriched in low NAR tumours (p < 0.25). Both cohorts showed higher Microenvironment Cell Population counter ‘Cytotoxic Lymphocytes’ in low NAR (p < 0.05) and more stromal cells (‘Endothelial Cells’, ‘Fibroblasts’; p < 0.05) in high NAR tumours. CD8 densities confirmed higher immune infiltration in low NAR tumours.
Discussion: Pre-treatment biopsies show consistent microenvironmental differences between high and low NAR tumours. While immune and stromal features are associated with response, the observed differences are insufficient to serve as standalone predictive biomarkers.
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BibTeX
@article{hillson2026immune,
title = {{Immune and stromal tumour biology associated with neoadjuvant radiotherapy response in locally advanced rectal cancer}},
author = {Lily V. S. Hillson and Ashley K. McCulloch and Ross K. McMahon and Phimmada Hatthakarnkul and Aula Ammar and Timothy S. Maughan and Enric Domingo and Sudhir B. Malla and Raheleh Amirkhah and James H. Park and Joanne Edwards and Philip D. Dunne and Sean M. O’Cathail and Campbell S. Roxburgh},
journal = {British Journal of Cancer},
year = {2026},
month = aug,
doi = {10.1038/s41416-026-03575-y},
url = {https://doi.org/10.1038/s41416-026-03575-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune and stromal tumour biology associated with neoadjuvant radiotherapy response in locally advanced rectal cancer
AU - Lily V. S. Hillson
AU - Ashley K. McCulloch
AU - Ross K. McMahon
AU - Phimmada Hatthakarnkul
AU - Aula Ammar
AU - Timothy S. Maughan
AU - Enric Domingo
AU - Sudhir B. Malla
AU - Raheleh Amirkhah
AU - James H. Park
AU - Joanne Edwards
AU - Philip D. Dunne
AU - Sean M. O’Cathail
AU - Campbell S. Roxburgh
PY - 2026
DA - 2026/08/18
JO - British Journal of Cancer
DO - 10.1038/s41416-026-03575-y
UR - https://doi.org/10.1038/s41416-026-03575-y
AB - Background: Response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC) is heterogeneous. The Neoadjuvant Rectal (NAR) score quantifies treatment response via tumour downstaging and nodal status and correlates with survival outcomes. This work set out to explore whether low NAR and high NAR tumours represent biologically distinct groups pre-treatment. Methods: Transcriptome microarrays quantified RNA expression within pre-treatment biopsies from LARC patients in GSE87211 and S:CORT consortium Grampian datasets. A validation cohort from the Beatson West of Scotland Cancer Centre was analysed using multiplex immunofluorescence and H&E-derived tumour-stromal ratios. Results: Seventeen MSigDB Hallmarks were enriched in high NAR tumours; ‘Epithelial-Mesenchymal Transition’ was notably enriched (padj < 0.001). Immune-related signatures were enriched in low NAR tumours (p < 0.25). Both cohorts showed higher Microenvironment Cell Population counter ‘Cytotoxic Lymphocytes’ in low NAR (p < 0.05) and more stromal cells (‘Endothelial Cells’, ‘Fibroblasts’; p < 0.05) in high NAR tumours. CD8 densities confirmed higher immune infiltration in low NAR tumours. Discussion: Pre-treatment biopsies show consistent microenvironmental differences between high and low NAR tumours. While immune and stromal features are associated with response, the observed differences are insufficient to serve as standalone predictive biomarkers.
SN - 0007-0920
SN - 1532-1827
ER -