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

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 and Rienk Offringa ()
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Daniel Baumann: German Cancer Research Center Heidelberg
Tanja Hägele: German Cancer Research Center Heidelberg
Julian Mochayedi: German Cancer Research Center Heidelberg
Jennifer Drebant: German Cancer Research Center Heidelberg
Caroline Vent: German Cancer Research Center Heidelberg
Sven Blobner: German Cancer Research Center Heidelberg
Julia Han Noll: German Cancer Research Center Heidelberg
Irena Nickel: German Cancer Research Center Heidelberg
Corinna Schumacher: German Cancer Research Center Heidelberg
Sophie Luise Boos: German Cancer Research Center Heidelberg
Aline Sophie Daniel: German Cancer Research Center Heidelberg
Susann Wendler: German Cancer Research Center Heidelberg
Michael Volkmar: German Cancer Research Center Heidelberg
Oliver Strobel: Heidelberg University Hospital
Rienk Offringa: German Cancer Research Center Heidelberg

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15979-2

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