Phenotype dictates outcome in synchronously resected primary colorectal tumours and matched liver metastases


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Kathryn Pennel1,Colin Steele1,Antonia Roseweir1,Rene Jackstadt2,Colin Nixon2,Xabier Cortes-Lavaud2,Campbell Roxburgh1,Hester van Wyk1,Donald McMillan1,Paul Horgan1,Owen Sansom2,Joanne Edwards1
1University of Glasgow, Glasgow, UK,2Cancer Research UK Beatson Institute, Glasgow, UK

Abstract

Background

5-year survival of patients with resectable colorectal liver metastases is 25-40%.  These patients do not generally benefit from immunotherapy although the majority are MMR proficient.  The view that high inflammatory infiltrate confers better prognosis, is overly simplified and it is likely the balance of the immune cells influences outcomes. As neutrophils are associated with poor prognosis and many express chemokine receptor CXCR2, we hypothesised that CXCR2-positive neutrophils drive stromally dense phenotypes resulting in poor outcome in some patients.

The current study examines, in-depth the relationships between, phenotype, cellular infiltrate, tumour cell signalling, clinicopathological features and outcomes in primary and secondary colorectal cancer.

Method

A unique cohort of synchronously resected primary colorectal tumours and matched liver metastases (n=46) were stained for markers of immune cell infiltration (CD4, CD8, CD68, MPO) and inflammatory signalling pathways (CXCL2, MMP9, HIF-1α, CRP) using immunohistochemistry. Tumours were phenotypically subtyped using Klintrup-Mäkinen grade (KM), tumour stroma percentage and Ki67 proliferation-index.

Results

Patients with immune phenotype (high KM grade) in both primary and secondary sites had the best prognosis and those with high intra-tumour-stroma exhibited worst prognosis (p=0.006). Presence of high levels of macrophages (CD68) associated with CXCR2 positive cells (p=0.018) and when these were both present in high numbers in both sites associated with stromal phenotype (p=0.021), tumour budding (p=0.002) and worse prognosis (p=0.002). Intra-tumour neutrophils (MPO) associated with CXCR2 expression(p=0.042). Macrophages, MMP9, and C-Reactive Protein expression increased between primary tumours and matched liver metastases, whereas lymphocyte infiltration (CD4, CD8), HIF-1α and CXCR2 expression was not observed to change.  

Conclusion

We observed an increase in cancer-specific survival in patients with high immune cell infiltrate when compared with patients with high levels of intra-tumour stroma.  Patients whose tumours exhibited this stromal phenotype had poor prognosis and were more likely to have infiltration of myeloid-cells including CXCR2-positive cells.