Abstract
534 Background: Immunotherapy has proven a largely ineffective treatment for MMR proficient colorectal cancer (CRC). Resistance to immunotherapy is due to the immunosuppressive microenvironment of colorectal cancer, with CMS4 disease proving most aggressive. Using a cohort of synchronously resected CRC and metastases we examine the relationships between common immune cells in the circulation and microenvironment of primary and secondary CRC to assess microenvironmental determinants of outcome in metastatic CRC. Methods: 46 patients that had synchronous resection of primary CRC and liver metastasis at Glasgow Royal Infirmary were included. The relationships between Neutrophil lymphocyte ratios (NLR), tissue MPO and CXCR2 positive neutrophils, CD68 positive macrophages, and CD8 positive effector T cells and Klintrup-Makinen (KM) scores were quantified. Results: There was correlation between MPO and CXCR2 positive neutrophils (r = 0.668, P = 0.014) within metastases and both of these factors were independently associated with poor outcome ( P < 0.001, P = 0.002 respectively). High CD8+ T cells numbers and KM grade in both primary and metastatic niches were independently associated with better outcome following synchronous resection (P < 0.01). High systemic neutrophil counts (NLR) were associated with poor outcome in patients having synchronous resection (P = 0.001) and correlated with neutrophil numbers in metastases (r = 0.329, P = 0.05). MPO (P < 0.001) and CXCR2 (P = 0.004) positive neutrophils within the metastatic niche and KM grade of the primary tumour (P = 0.002) remained negative prognostic indicators on multivariate analysis. Conclusions: While CD8+ T cells impact positively on prognosis, the negative impact of neutrophils within the metastatic niche is the strongest determinant of outcome in synchronously resected CRC. This study raises questions as to the heterogeneity of neutrophils within primary and metastatic colorectal cancer and whether negatively prognostic neutrophils can be phenotyped and therapeutically targeted.
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