AMMF’s Virtual 2021 European Cholangiocarcinoma Conference

Abstract No 14

Prognostic value of tumour-infiltrating CD68+ macrophages is dependent upon location within cholangiocarcinoma tumours

I.U Egbuniwe1*, U. Rastovic1, M. Persson2, K.J Hunter3, A.M Grabowska1, D.O Bates1, PS Jayaraman1, K. Gaston1

1.Division of Cancer and Stem Cells, University of Nottingham
2.Centre of Evidence Based Dermatology, University of Nottingham
3.Cancer Research UK Birmingham Centre, University of Birmingham
* Corresponding author – Dr Isioma U. Egbuniwe, Division of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, UK;

Cholangiocarcinoma (CCA) tumours are increasingly being recognised as having an immune component. However, not many studies have investigated immune-related mechanisms of disease pathogenesis and progression in CCA. We therefore aimed to investigate the potential role of immune cells in CCA pathology. Using immunohistochemistry, we first analyzed formalin-fixed, paraffin-embedded CCA tumours where we found enrichment of CD3+ T cells, i.e. total T cells (n=20; mean=327; p=0.0002) and CD68+ macrophages (n=17; mean=167; p<0.0001) within tumour stroma compared with matched non-tumour bile duct stroma. Helper (CD4+) and cytotoxic (CD8+) T cells subsets were also found to be enriched within tumour stroma. We next investigated whether the presence of tumour-infiltrating immune cells (assessed histologically) correlated with clinical outcome (overall survival; OS) in patients diagnosed with CCA. For this we conducted a systematic review and meta-analysis of existing literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines(1). CD68+ macrophages and CD8+ (cytotoxic) T cell infiltration into CCA tumours were found to be most significantly associated with overall patient survival. Notably, the prognostic value of CD68+ macrophages was dependent upon location within tumours, with “centrally located” macrophages correlating to worse OS (HR=1.90; 95%CI=1.19 – 3.04), while macrophage presence at the tumour “invasive front” correlated to better OS (HR=0.66; 95%CI=0.42 – 1.03). This association was lost when tumour sections were evaluated in their entirety (HR=1.29; 95%CI=1.00 – 1.66). Finally, using Nanostring™ Digital Spatial Profiling, we preliminarily undertook spatially-resolved analysis of immune protein signatures within CCA tumours (n=2). Quantification and cluster analyses corroborated the differential presence of CD68+ macrophages within distinct tumour regions, and further revealed distinct clustering patterns between CD68+ macrophages and the immune checkpoint molecule B7-H3. Our findings highlight the importance of precise spatial interrogation in the evaluation of CCA tumours.

1.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.

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