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.
Highlights
The role of myeloid cells in promoting tumour progression by contributing to an immunosuppressive microenvironment has been well-established[1,2,3,4]
Tumour growth is reduced in MK2ΔCD11c mice upon activation of endogenous dendritic cells (DC) by delivery of tumour antigen and LPS
Whereas delivery of LPS alone did not affect tumour size in MK2ΔCD11c mice versus WT controls, the combination of toll-like receptor (TLR) agonist and tumour antigen led to a significant reduction and sustained control of tumour growth in MK2ΔCD11c mice and even resulted in tumour clearance in 3 out of 6 animals within 12 days post-tumour cell injection (Fig. 1a,b and Supplementary Fig. 1a)
Summary
The role of myeloid cells in promoting tumour progression by contributing to an immunosuppressive microenvironment has been well-established[1,2,3,4]. One hallmark of altered myelopoiesis is the skewing of dendritic cell (DC) differentiation to an expansion of myeloid-derived suppressor cells (MDSCs)[6] and multiple tumour-derived factors have been identified to drive such myeloid deviation[7] The accumulation of this heterogeneous population of immature myeloid cells and progenitors is strongly associated with tumour progression and unfavourable prognosis across multiple cancer types[8,9]. MK2 acts as cell cycle regulator, coming into play upon p53 mutation[30,31] In this context, MK2 and several of its downstream effectors have been identified to mediate resistance of tumours to therapy-induced apoptosis[28,32]. Taking into consideration its diverse functions, whether DC-expressed MK2 modulates anti-tumour immune responses has not been answered to date
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