MAPK regulation of DC IL-12 family is exploited by melanoma to subvert Th-1 priming

• Main Author: Mulcahy, Lori Ann
• Published: University of Nottingham 2008
• Subjects: 616.994
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490963

Effective anti-cancer responses are mediated by an IFN-y and Twi type immune profile. Crucial to the induction of IFN-y are the cytokines Il-27 and Il-12. Il-27 initiates Twi differentiation from naive T-cells and Il-12 quickly takes over to drive IFN-y and expand the TH-i population. Dendritic cells (DC) present antigen and instruct lymphocytes, this role places them at the apex of adaptive immunity. They are the major source of Il-12 and Il-27. DC conditioning by the microenvironment upon antigen uptake significantly alters both the resultant cytokine response and T-cell polarisation The tumour microenvironment is a.unique compartment where a high concentration of pro-angiogenic and inflammatory suppressor modulators are concentrated. It is in this region that DC encounter tumour antigens and inflammatory signals are switched off. Il-12 is inhibited in patients of melanoma and other tumours and the underlying molecular mechanisms are of considerable interest to cancer immunologis~s. Here the investigation of melanoma mediated Il-12 suppression revealed that both Il-12 and Il-27 are targeted. Cytokine inhibition directly limits T-ceIlIFN-y release and the TH-l population size, reinforcing the central role of Il-12 in anticancer responses. Il-12 is highly regulated and there are several mechanisms able to switch off IL-12 expression. Melanoma acts in an Il-iO independent manner and does not alter global phenotypic DC maturation. Selected TLR ligands and pathogen derived molecules activate the MAPK ERK pathway and down-regulate IL-12 in a manner strikingly similar to melanoma. Investigation of the MAPK revealed hyper-activation of ERK is responsible for IL- 12 suppression and using a specific inhibitor of ERK recovers melanoma suppressed IL-12 expression from DC. This work is the first to demonstrate that a signalling pathway used to regulate inflammation and exploited by pathogens is also.a mechanism of tumour immune escape. One of the major hurdles for effective DC based immunotherapy is functional inhibition in the tumour setting. This work suggests that the application of ERK inhibitors, already clinically approved, could be a useful tool in overcoming this issue.