Interferon-related signalling dictates prognosis in the fibroblast-rich subtype of stage II and III colon cancer


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Amy McCorry1,Rene Jackstadt2,Dustin Flanagan2,S:cort Consortium3,ACRCelerate Consortium4,Owen Sansom2,Mark Lawler1,Philip Dunne1
1Queen's University Belfast,2Cancer Research UK Beatson Institute,3S:CORT Consortium,4ACRCelerate

Abstract

Background

Despite improvements in standard-of-care treatment, patients with stage II and stage III colon cancer (CC) still experience disease relapse rates of 20% and 36% respectively. High levels of stroma (particularly fibroblasts) has been associated with a poor-prognostic group of CC, which has been identified using either molecular or histological subtyping. There have been inconsistent data concerning the benefit of standard 5FU-based adjuvant chemotherapy in patients with high-fibroblast (HiFi) tumours. Additionally, understanding of the specific biological signalling driving the poor outcome in HiFi tumours is limited, reducing opportunities for selection of more suitable therapeutic options.

Method

A cohort of stage II patients (n=215), who had not received any adjuvant chemotherapy, were assigned a fibroblast score using single-sample gene set enrichment analysis. The cohort was stratified into high-fibroblast (HiFi) and low-fibroblast (LoFi). Stratification based on relapse-free survival within the HiFi group allowed for in silico discovery, interrogation and independent validation of the biology underpinning relapse.

Results

In line with previous findings, the HiFi group had significantly poorer relapse-free survival compared to the LoFi group (p = 0.00779). Analyses in our discovery cohort (n=215) and validation in an independent dataset (n=258) revealed that prognosis in HiFi tumours is associated with interferon-related signalling, indicative of specific populations of cells present in the tumour microenvironment. This HiFi group do not appear to benefit from the addition of 5FU-based chemotherapy in the adjuvant setting, which is in line with CC in vitro and in vivo models of this stromal-rich group. Importantly, direct targeting of immune lineages in HiFi models in vivo significantly reduces distant metastases.

Conclusion

We have identified that interferon-related signalling and select populations of innate immune cells are responsible for reducing the risk of recurrence, in the otherwise poor-prognostic HiFi subtype of CC. Ongoing work is now focused on further validation of novel therapies for HiFi patients.