دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer.
المؤلفون: Corry SM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., McCorry AM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Lannagan TR; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK., Leonard NA; Lambe Institute for Translational Research, College of Medicine Nursing and Health Sciences, National University of Ireland, Galway, Ireland.; Discipline of Pharmacology & Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland., Fisher NC; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Byrne RM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Tsantoulis P; Université de Genève, Geneva, Switzerland., Cortes-Lavaud X; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK., Amirkhah R; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Redmond KL; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., McCooey AJ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Malla SB; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Rogan E; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Sakhnevych S; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Gillespie MA; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., White M; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Richman SD; Leeds Institute of Medical Research, University of Leeds, Leeds, UK., Jackstadt RF; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK.; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) and Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ), Heidelberg, Germany., Campbell AD; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK., Maguire S; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., McDade SS; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Longley DB; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Loughrey MB; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.; Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK.; Centre for Public Health, Queens University Belfast, Belfast, UK., Coleman HG; Centre for Public Health, Queens University Belfast, Belfast, UK., Kerr EM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Tejpar S; Digestive Oncology Unit, University Ospital Gasthuisberg, Leuven, Belgium., Maughan T; Department of Oncology, University of Oxford, Oxford, UK., Leedham SJ; Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK., Small DM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Ryan AE; Lambe Institute for Translational Research, College of Medicine Nursing and Health Sciences, National University of Ireland, Galway, Ireland.; Discipline of Pharmacology & Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland., Sansom OJ; Cancer Research UK, Beatson Institute for Cancer Research, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Lawler M; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Dunne PD; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK p.dunne@qub.ac.uk.
مؤلفون مشاركون: S:CORT and ACRCelerate consortia
المصدر: Gut [Gut] 2022 Dec; Vol. 71 (12), pp. 2502-2517. Date of Electronic Publication: 2022 Apr 27.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: British Medical Assn Country of Publication: England NLM ID: 2985108R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-3288 (Electronic) Linking ISSN: 00175749 NLM ISO Abbreviation: Gut Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London, British Medical Assn.
مواضيع طبية MeSH: Biomarkers, Tumor*/genetics , Colonic Neoplasms*/pathology, Humans ; Stromal Cells/pathology ; Neoplasm Recurrence, Local/prevention & control ; Neoplasm Recurrence, Local/pathology ; Prognosis
مستخلص: 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.
Competing Interests: Competing interests: ML has received honoraria from Pfizer, EMF Serono and Roche for presentations unrelated to this work; ML has received an unrestricted educational grant from Pfizer for research unrelated to this work. PT has received honoraria and travel expenses from BMS, Merck, Roche, Lilly and Sanofi-Aventis for contributions that are not related to the present work. The authors declare no other potential conflicts of interest.
(© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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معلومات مُعتمدة: 110371/Z/15/Z United Kingdom WT_ Wellcome Trust; MR/S021205/1 United Kingdom MRC_ Medical Research Council; A26825 United Kingdom CRUK_ Cancer Research UK; 24387 United Kingdom CRUK_ Cancer Research UK; BB/T002824/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 206314/Z/17/Z United Kingdom WT_ Wellcome Trust; G0400302 United Kingdom MRC_ Medical Research Council; MC_PC_17117 United Kingdom MRC_ Medical Research Council; MR/M016587/1 United Kingdom MRC_ Medical Research Council; 15333 United Kingdom CRUK_ Cancer Research UK; 29834 United Kingdom CRUK_ Cancer Research UK; A28223 United Kingdom CRUK_ Cancer Research UK; A17196 United Kingdom CRUK_ Cancer Research UK; A31287 United Kingdom CRUK_ Cancer Research UK; 26045 United Kingdom CRUK_ Cancer Research UK; A21139 United Kingdom CRUK_ Cancer Research UK
فهرسة مساهمة: Keywords: ADJUVANT TREATMENT; CANCER; COLON CARCINOGENESIS; COLORECTAL CANCER
المشرفين على المادة: 0 (Biomarkers, Tumor)
تواريخ الأحداث: Date Created: 20220428 Date Completed: 20221109 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC9664095
DOI: 10.1136/gutjnl-2021-326183
PMID: 35477539
قاعدة البيانات: MEDLINE
الوصف
تدمد:1468-3288
DOI:10.1136/gutjnl-2021-326183