4.8 Article

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

期刊

GUT
卷 71, 期 12, 页码 2502-2517

出版社

BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2021-326183

关键词

CANCER; COLON CARCINOGENESIS; COLORECTAL CANCER; ADJUVANT TREATMENT

资金

  1. CRUK [A29834]
  2. International Accelerator Award, ACRCelerate - Cancer Research UK [A26825, A28223]
  3. FC AECC [GEACC18004TAB]
  4. AIRC [22795]
  5. CRUK core funding (CRUK Beatson Institute) [A21139, A17196, A31287]
  6. Queen's University Belfast Foundation grant
  7. joint MRC-CRUK Stratified Medicine Programme Grant (S:CORT) [MR/M016587/1]
  8. Health Data Research UK Substantive Site grant
  9. Patrick G Johnston Centre for Cancer Research Applied Genomics Hub for Bioinformatics Support
  10. CRUK Belfast Experimental Cancer Medicine Centre

向作者/读者索取更多资源

This study identifies and validates a HiFi-specific prognostic signature (HPS) based on STAT1-related signaling in the stroma-rich subtype of colon cancer. The HPS is associated with immune cell and antigen processing in stroma-rich colon cancer and treatment with the TLR3 agonist poly(I:C) can enhance the HPS signaling and reduce liver metastases.
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.

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