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, 71(12), pp. 2502-2517. (doi: 10.1136/gutjnl-2021-326183) (PMID:35477539) (PMCID:PMC9664095)

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: Published
• 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: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• 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 71(12): 2502-2517
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
301989		ACRClerate: Colorectal Cancer Stratified Medicine Network	Owen Sansom	Cancer Research UK (CRUK)	C7932/A26825	CS - Beatson Institute for Cancer Research