Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer

Corry, S. M. et al. (2022) Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer. Gut, (doi: 10.1136/gutjnl-2021-326183) (PMID:35477539) (Early Online Publication)

[img] Text
270354.pdf - Published Version
Available under License Creative Commons Attribution.

9MB

Abstract

Objective: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. Design: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. Results: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). Conclusion: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:White, Dr Mark and Sansom, Professor Owen and Campbell, Dr Andrew
Authors: Corry, S. M., McCorry, A. M.B., Lannagan, T. R.M., Leonard, N. A., Fisher, N. C., Byrne, R. M., Tsantoulis, P., Cortes-Lavaud, X., Amirkhah, R., Redmond, K. L., McCooey, A. J., Malla, S. B., Rogan, E., Sakhnevych, S., Gillespie, M. A., White, M., Richman, S. D., Jackstadt, R.-F., Campbell, A. D., Maguire, S., McDade, S. S., Longley, D. B., Loughrey, M. B., Coleman, H. G., Kerr, E. M., Tejpar, S., Maughan, T., Leedham, S. J., Small, D. M., Ryan, A. E., Sansom, O. J., Lawler, M., and Dunne, P. D.
College/School:UNSPECIFIED
Journal Name:Gut
Publisher:BMJ Publishing Group
ISSN:0017-5749
ISSN (Online):1468-3288
Published Online:27 April 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Gut 2022
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301989ACRClerate: Colorectal Cancer Stratified Medicine NetworkOwen SansomCancer Research UK (CRUK)C7932/A26825CS - Beatson Institute for Cancer Research