Using a melanoma tumor model in a myeloid-lineage (CD11c+) knockout of MAPK-activated protein kinase 2 (MK2), Soukup et al. concluded that MK2 is an intracellular checkpoint that promotes a suppressive dendritic cell (DC) phenotype. Knockout of MK2 reduces the accumulation of myeloid-derived suppressive cells and promotes the expansion of mature CD103+ DCs, thus enhancing CD8+ T cell priming, functionality, and infiltration, and reducing tumor growth in the context of Toll-like receptor agonist and tumor antigen.
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.
Author Info: (1) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. klara.soukup@unil.ch. Department of Fundamental Oncology, Ludwig Instit
Author Info: (1) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. klara.soukup@unil.ch. Department of Fundamental Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. klara.soukup@unil.ch. (2) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. (3) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. (4) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. (5) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. (6) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. (7) Bioinformatics, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. (8) Institute for Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. (9) Institute for Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. (10) Tumour Immunology, St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria. alexander.dohnal@apeiron-biologics.com. APEIRON Biologics AG, Vienna, Austria. alexander.dohnal@apeiron-biologics.com.
