No abstract

Maintaining dendritic cells (DC) in a state of dysfunction represents a key mechanism by which tumour cells evade recognition and elimination by the immune system. Limited knowledge about the intracellular mediators of DC dysfunction restricts success of therapies aimed at reactivating a DC-driven anti-tumour immune response. Using a cell type-specific murine knock-out model, we have identified MAPK-activated protein kinase 2 (MK2) as a major guardian of a suppressive DC phenotype in the melanoma tumour microenvironment. MK2 deletion in CD11c+ cells led to an expansion of stimulatory CD103+ DCs, mounting a potent CD8+ T cell response that resulted in elimination of highly aggressive B16-F10 tumours upon toll-like receptor (TLR) activation in the presence of tumour antigen. Moreover, tumour infiltration by suppressive myeloid cells was strongly diminished. These insights into the regulation of DC functionality reveal MK2 as a targetable pathway for DC-centred immunomodulatory cancer therapies.

The MAPK signaling pathway represents a central player in inflammatory processes. As a downstream target of p38, MAPK-activated protein kinase 2 (MK2) contributes to signal transduction regulating the expression and translation of various targets, among them several cytokines such as tumor necrosis factor (TNF) α. While MK2 was shown to promote an inflammatory macrophage phenotype, we have reported its Th1-attenuating function in dendritic cells (DCs). These observations of differential regulatory functions prompted us to investigate MK2 in the context of DCs and other myeloid cells in the tumor microenvironment. Murine DCs lacking MK2 activity exhibit an enhanced potential to differentiate Th1 cells upon Toll-like receptor (TLR) ligation in vitro and in vivo. In line with this finding, we observe significantly reduced B16.F10 melanoma growth in CD11cCre-MK2fl/fl mice upon DC activation by administration of lipopolysaccharide (LPS) together with whole tumor cell lysate as compared to wildtype littermate controls. Interestingly, CD11cCre-MK2fl/fl mice show an overall reduced myeloid cell tumor infiltration. Looking at MK2 expression in DCs isolated from orthotopic B16.F10 tumor-bearing mice, we find elevated MK2 levels in tumor-resident as opposed to splenic DCs, which has also been confirmed in a model of intracranial glioma (GL-261). This MK2 up-regulation in glioma-infiltrating DCs is associated with an enhanced expression of IL-10. Furthermore, tumor-resident myeloid-derived suppressor cells (MDSCs) show elevated MK2 expression, further underlining its potential involvement in immunosuppressive mechanisms in the myeloid lineage. In DCs we have observed cross-regulation of MAPK signaling by MK2, which promotes ERK1/2 while attenuating p38 activation and is further implicated to enhance STAT3 phosphorylation – all together contributing to a tolerogenic DC phenotype. Therefore we are now looking to unravel mechanisms by which MK2 impacts on signaling networks involved in myeloid immunosuppression in the tumor microenvironment. Our data contrast the previously described role of MK2 in pro-inflammatory mechanisms of the p38 signaling route and suggest an additional immunosuppressive feedback function in myeloid cells, which might be exploited by tumor cells to escape immune recognition and elimination. These indications are particularly interesting with regard to glioma, since the glioma microenvironment has been shown to be rich in various cytokines promoting favourable conditions for tumor growth. Finally, MK2 represents a promising target for combination therapy, as it has been reported to mediate chemo- as well as radioresistance in different types of tumors. Nevertheless, its function in tumor-infiltrating immune cells remains to be elucidated. We therefore aim to contribute to a deeper understanding of the complex interplay between extra- and intracellular signaling molecules regulating tumor as well as immune cell phenotypes. Citation Format: Klara Soukup, Angela Halfmann, Fiona Poyer, Katharina Martin, Bernadette Blauensteiner, Bastien Huber, Mario Kuttke, Gernot Schabbauer, Lydia Zopf, Jelena Zinnanti, Alexander Michael Dohnal. MAPK-activated protein kinase MK2 exerts immune regulatory functions in the microenvironment of orthotopic tumors. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A43.