ISG Winter Meeting 2015
Second Prize Basic Science
St. Vincent’s University Hospital, Dublin
Metastatic Microenvironment of Human Liver, Characterised by Increased Levels of IL6, VEGF and GMCSF, Blocks Interferon g Production by Natural Killer Cells
Hand F1,2, Harmon C2, Elliott L3, Caizza F3, Nolan N2, Geoghegan J1, Ryan EJ3, O’Farrelly C2
1National Liver Unit, St.Vincent’s Hospital, Elm Park, Dublin . 2School of Biochemistry & Immunology and School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin. 3Centre for Colorectal Disease, School of Medicine and Medical Sciences, University College Dublin & St. Vincent’s Hospital, Elm Park, Dublin.
The healthy liver is immunologically equipped for effective immune surveillance, with repertoires of potent anti tumour lymphoid populations including NK cells, CD8+ T lymphocytes and iNKT cells. These populations are functionally compromised in liver metastases and are therefore important immunotherapeutic targets. Here we explore the hypothesis that the immune micro environment of metastatic liver is responsible for compromised NK function thereby contributing to metastatic development.
To examine the cytokine and growth factor milieu of metastatic and healthy liver and test its effect on Natural Killer cell activity
Twenty-five patients with colorectal liver metastases (CRLM) undergoing liver resection were prospectively recruited to this study. Biopsies of freshly resected tumour, tumour adjacent liver and liver at the distal resection margin were cultured in vitro to obtain metastatic conditioned media (CM). Using an antibody array, metastatic CM was screened for 102 cytokines and proinflammatory mediators and compared to CM from healthy control liver. Differentially expressed cytokines (n=12) were quantified using luminex-based multiplex analysis. The effect of metastatic and healthy CM on NK function was assessed.
Healthy liver biopsies secreted high levels of diverse cytokines and growth factors. Several cytokines demonstrated altered expression in the metastatic microenvironment. Metastatic liver was characterised by increased expression of several proinflammatory mediators including IL6 (p=0.03), VEGF (p=0.006) and RANTES (p=0.006). Furthermore, LIF (p=0.0008) GMCSF (p=0.04) and IP10 (0.01) levels were increased at the distal resection margin when compared to control indicating that the whole organ, not jus the immediate environment was responding immunologically to the tumour. CM from tumour-bearing liver tissue , inhibited IFNγ production by Natural Killer Cells.
Healthy human liver has a highly evolved anti-tumour immune repertoire which is maintained by a complex cytokine environment with pro-inflammatory and immunosuppressive activity. The altered cytokine profile of the metastatic microenvironment inhibits NK cell function, perhaps potentiating tumour growth and metastatic recurrence.