Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer. Issue 12 (27th April 2022)

• Record Type: Journal Article
• Authors: Corry, Shania M; McCorry, Amy MB; Lannagan, Tamsin RM; Leonard, Niamh A; Fisher, Natalie C; Byrne, Ryan M; Tsantoulis, Petros; Cortes-Lavaud, Xabier; Amirkhah, Raheleh; Redmond, Keara L; McCooey, Aoife J; Malla, Sudhir B; Rogan, Emily; Sakhnevych, Svetlana; Gillespie, Michael A; White, Mark; Richman, Susan D; Jackstadt, Rene-Filip; Campbell, Andrew D; Maguire, Sarah; McDade, Simon S; Longley, Daniel B; Loughrey, Maurice B; Coleman, Helen G; Kerr, Emma M; Tejpar, Sabine; Maughan, Timothy; Leedham, Simon J; Small, Donna M; Ryan, Aideen E; Sansom, Owen J; Lawler, Mark; Dunne, Philip D;
• Is Part Of: Gut. Volume 71:Issue 12(2022)
• Page Start: 2502
• Page End: 2517
• Publication Date: 2022-04-27
• Subjects: CANCER -- COLON CARCINOGENESIS -- COLORECTAL CANCER -- ADJUVANT TREATMENT; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2021-326183
• Languages: English
• ISSNs: 0017-5749

Abstract

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.