1. Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy.
- Author
-
Baumann D, Hägele T, Mochayedi J, Drebant J, Vent C, Blobner S, Noll JH, Nickel I, Schumacher C, Boos SL, Daniel AS, Wendler S, Volkmar M, Strobel O, and Offringa R
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols chemistry, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Pharmacological metabolism, CD40 Antigens immunology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Drug Synergism, Gene Expression Profiling, Humans, Macrophages drug effects, Macrophages immunology, Male, Mice, Mice, Inbred C57BL, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transcriptome genetics, Adenocarcinoma drug therapy, Antibodies, Monoclonal pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, CD40 Antigens agonists, Carcinoma, Pancreatic Ductal drug therapy, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.
- Published
- 2020
- Full Text
- View/download PDF