IL-6 Activities in the Tumour Microenvironment. Part 1

The predominant role of IL-6 in cancer is its key promotion of tumour growth. IL-6 binds IL-6 receptor (IL-6R) and the membrane-bound glycoprotein gp130. The complex I-6/IL-6R/gp130 starts the Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3) or JAK/STAT3 pathway. IL-6R exits in two forms: a membrane-bound IL-6Rα subunit (mIL-6R) that participates in classic signalling pathway and soluble IL-6R subunit (sIL-6R) engaged in trans-signalling. The pro-tumour functions of IL-6 are associated with STAT3, a major oncogenic transcription factor that triggers up-regulation of target genes responsible for tumour cell survival. IL-6 combined with TGF-β induces proliferation of pathogenic Th17 cells. The anti-tumour function of IL-6 is the promotion of anti-tumour immunity. IL-6 trans-signaling contributed to transmigration of lymphocytes in high endothelial venules (HEV). Dendritic cell (DC) secreted IL-6 in the lymph node influences the activation, distribution and polarisation of the immune response. Elevated serum levels of IL-6 and increased expression of IL-6 in tumour tissue are negative prognostic marker for patients’ survival

Intratumoural expression of IL-6/STAT3, IL-17 and FOXP3 immune cells in the immunosuppressive tumour microenvironment of colorectal cancer Immune cells-positive for IL-6, STAT3, IL-17 and FOXP3 and colorectal cancer development

AbstractImmune cells in the tumour microenvironment (TME) interact with each other and with tumour cells to promote tumour development. IL-6/STAT3 pathway induces and maintains mainly pro-tumour TME. Macrophages and lymphocytes are positive for IL-6, STAT3 and IL-17, while FoxP3 cells are mainly regulatory cells. IL-17+ and FoxP3+ immune cells have impact on gut inflammation and tumourigenesis. The aim of this study was to determine IL-6+, STAT3+, IL-17+ and FoxP3+ immune cells in colorectal cancer (CRC) TME and explore their association with clinicopathological parameters and mismatch repair (MMR) status. The investigated samples were collected from 104 CRC patients. Immunohistochemistry for the aforementioned markers and microsatellite instability (MSI) markers was performed. MSI testing was used. The investigated immune cells were significantly more in the invasive front (IF) as compared to tumour stroma (TS). IL-6+ and STAT3+ immune cells were more in the early tumour stages as compared to advanced stages. IL-17+ and IL-6+ immune cells were more in well and moderately differentiated cancers. IL-6+, STAT3+ and IL-17+ immune cells prevailed in the TME in microsatellite stable patients and only FoxP3+ cells were fewer there. Higher numbers of STAT3+ cells correlated with longer survival. These results support the suggestion that the transition of normal colonic mucosa to CRC is marked by a shift of Th programme, leading to accumulation of Th17 cells and Tregs that sustain tumour cell growth through the IL-6/STAT3 signalling pathway