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

Shania M Corry, Amy MB McCorry, Tamsin R M Lannagan, Niamh A Leonard, Natalie C Fisher, Ryan M Byrne, Petros Tsantoulis, Xabier Cortes-Lavaud, Raheleh Amirkhah, Keara L Redmond, Aoife J McCooey, Sudhir B Malla, Emily Rogan, Svetlana Sakhnevych, Michael Gillespie, Mark White, Susan Richman, Rene Jackstadt, C. Andrew Campbell, Sarah MaguireSimon S McDade, Daniel B Longley, Maurice B Loughrey, Helen G Coleman, Emma M Kerr, Sabine Tejpar, Tim Maughan, Simon Leedham, Donna M Small, Aideen Ryan, Owen J. Sansom, Mark Lawler, Philip D Dunne*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 utilise 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 - 0.466). Utilizing 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.

Original languageEnglish
Pages (from-to)2502–2517
Number of pages16
Issue number12
Early online date27 Apr 2022
Publication statusPublished - 07 Nov 2022


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