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Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy

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...

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Main Authors: Baumann, Daniel (Author) , Hägele, Tanja (Author) , Mochayedi, Julian (Author) , Drebant, Jennifer (Author) , Vent, Caroline (Author) , Blobner, Sven (Author) , Noll, Julia Han (Author) , Nickel, Irena (Author) , Schumacher, Corinna (Author) , Boos, Sophie Luise (Author) , Daniel, Aline Sophie (Author) , Wendler, Susann (Author) , Volkmar, Michael (Author) , Strobel, Oliver (Author) , Offringa, Rienk (Author)
Format: Article (Journal)
Language:English
Published: 01 May 2020
In: Nature Communications
Year: 2020, Volume: 11
ISSN:2041-1723
DOI:10.1038/s41467-020-15979-2
Online Access:Verlag, Volltext: https://doi.org/10.1038/s41467-020-15979-2
Verlag: https://www.nature.com/articles/s41467-020-15979-2
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Author Notes:Daniel Baumann, Tanja Hägele, Julian Mochayedi, Jennifer Drebant, Caroline Vent, Sven Blobner, Julia Han Noll, Irena Nickel, Corinna Schumacher, Sophie Luise Boos, Aline Sophie Daniel, Susann Wendler, Michael Volkmar, Oliver Strobel, Rienk Offringa
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Summary: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.
Item Description:Gesehen am 08.07.2020
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-020-15979-2

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