Immune activity during progression of human colorectal cancer

Doctoral thesis English OPEN
Costa Bento, Diana Filipa (2016)
  • Subject: RC0254
    mesheuropmc: digestive system diseases

Colorectal cancer (CRC) patients survive and stay free of disease for longer\ud after surgery if their primary tumours were infiltrated with an increased\ud density of T cells. Studies of breast tumours and melanoma have also shown\ud that the presence of specialised blood vessels named high endothelial\ud venules (HEVs), within tumours are associated with a high density of\ud infiltrating T cells and a positive prognosis. It is therefore possible, that\ud presence of HEVs within CRC is associated with a high density of infiltrating\ud T cells and a good patient outcome.\ud To test this hypothesis, primary tumours, resected from sixty-two CRC\ud patients were analysed for the presence of HEVs. These were studied with\ud respect to the numbers and distribution of intra-tumoural T cells as well as\ud tumour stage and patient survival. The results showed that HEV developed\ud in response to CRC but were found within the extra-tumoural area and not\ud the tumour mass. HEVs were also always present within a concentration of T\ud and B cells, namely lymphoid aggregates which resemble ectopic lymphoid\ud structures (ELS). These ELS were associated with more advanced disease\ud and hence did not necessarily identify patients with a better prognosis.\ud Recent studies have suggested that the type of T cells infiltrating the\ud tumours is a determinant for patient outcome indicating that not all T cells\ud confer benefit. IL-17A producing T cells are thought to drive CRC\ud development. Moreover, our laboratory has previously shown that detection\ud of a CEA (Carcinoembryonic antigen)-specific T cell response by in vitro\ud secretion of IFN-γ is associated with tumour recurrence whereas the\ud opposite is true for the 5T4 tumour antigen. This study therefore set out to\ud determine whether IL-17A producing T cells are present at higher\ud frequencies in CRC compared to normal bowel and whether IL-17Aproducing\ud T cells are CEA-specific.\ud The experiments revealed that IL-17A-producing T cells are present at a\ud higher frequency within CRCs, but the prevalence of Th17 responses\ud specific for 5T4 was slightly higher than for CEA, implying that IL-17A\ud secretion by CEA-specific T cells was not responsible for the tumour\ud recurrence. Tumours from CEA-responsive patients were less immunogenic\ud than those from CEA non-responsive patients reflecting the aggressiveness\ud of the tumour.
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