Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer-related deaths. For patients, current therapy primarily entails surgical removal of the tumour and chemotherapy, to which tumours are variably responsive.
The immune system can be a double-edged sword in cancer because it can both combat and contribute to tumour development. The Powrie Group at the Kennedy Institute of Rheumatology were interested understanding the role of molecule IL-22, produced by immune cells, and to identify mechanisms by which it might influence CRC.
Their research published in Clinical Cancer Research found a link between the receptor for IL-22 and a mutation in the gene KRAS, showing that they work cooperatively to promote excessive growth and division of tumour cells. This is hypothesised to explain why prognosis is significantly worse for patients whose tumours have both a mutation in KRAS and high expression of the IL-22 receptor.
"IL-22 is critical in maintaining immune homeostasis by triggering the release of anti-microbial substances and the healthy turnover of the cells that line the gut," said Beth Mann, Postdoc Researcher in Gut T Cell Regulation at the Kennedy Institute for Rheumatology, University of Oxford. "Nonetheless, there is growing evidence that IL-22 can be detrimental by promoting excessive proliferation of tumour cells. We have shown this to be particularly true for cancer cells that have a mutation in the gene KRAS, which is present in 40-45% of colorectal tumours."
KRAS-mutant tumours are particularly poorly responsive to certain standard therapies and despite considerable efforts, the development of KRAS inhibitors has been largely unsuccessful. These latest results mean that for patients whose tumours have a KRAS mutation and high amounts of IL-22 receptor closer monitoring and more aggressive or alternative therapy strategies (like blocking IL-22) may be beneficial.
The research was primarily funded by an 'Experimental Medicine Challenge Grant' from the MRC and CRUK Grand Challenge funding (OPTIMISTICC).