Biliary Tract Cancers (BTC) are inflammatory cancers with derangement of cytokines and recruitment of immune cells. Here we investigate if a transcriptomic immune profile (IP) is activated in BTC and represents a feature of biological behaviour.
RNA was extracted by tumour tissues (TT) and matched adjacent tissues (AT). IP of 700+ immune-related transcripts was performed in TT and AT of 24 BTCs by nCounter assay. CD80 expression was assessed by immunohistochemistry (IHC). Cox regression analysis and Kaplan Meier methods were used to correlate with Relapse Free Survival (RFS) and derive a prognostic gene signature.
132 transcripts were aberrantly expressed in TT vs AT. Ingenuity Pathway Analysis showed that leucocyte migration was the top function annotation. De-regulation of PDZ Binding Kinase (PBK) in TT appeared to differentiate cases with worse prognosis (nCounter p:0.08; Taqman p:0.07). We derived a list of genes whose expression was associated with RFS. We observed that risk of recurrence was associated with a greater number of genes deregulated in AT than in TT. We shortlisted genes that maintained statistical significance at multivariate analysis (gene expression, tumour site, adjuvant chemotherapy (AC) and R0/1 resection). We observed correlation between high expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) in the AT and RFS (p:0.0004). Cases with low CTLA4 had reduced expression of CD80, while cases with high CTLA4 had increased CD80 expression. IHC expression of CD80 varied in TT and AT. No association was seen between AT CD80 expression and RFS. However, CD80 expression seemed to differentiate prognosis in patients who did not receive AC (p:0.01), suggesting that activation of this pathway may promote relapse and may be affected from adjuvant treatment. Number of CD8+ and CD4+ cells did not correlate with RFS. We also derived a immuno-gene signature that could significantly differentiate relapsed cases and was an independent prognostic factor (HR 29.43, p:0.001).
We showed that IP is deregulated in the AT of resected BTC and correlates with relapse suggesting that deregulation of immune infiltrate in the normal tissue creates a favourable soil for cancer cell growth.
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Legal entity responsible for the study
Institute of Cancer Research.
All authors have declared no conflicts of interest.