Journal Article

DKFZ-2020-00959

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy.

Baumann, D. (First author)DKFZ* ; Hägele, T.DKFZ* ; Mochayedi, J.DKFZ* ; Drebant, J.DKFZ* ; Vent, C.DKFZ* ; Blobner, S.DKFZ* ; Noll, J. H.DKFZ* ; Nickel, I.DKFZ* ; Schumacher, C.DKFZ* ; Boos, S. L.DKFZ* ; Daniel, A. S.DKFZ* ; Wendler, S.DKFZ* ; Volkmar, M.DKFZ* ; Strobel, O. ; Offringa, R. (Last author)DKFZ*

2020
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-020-15979-2

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.

Note: #EA:D220#LA:D200#

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Contributing Institute(s):

1. Molekulare Grundlagen Gastrointestinaler Tumoren (D200)
2. DKFZ -Bayer Healthcare Joint (D220)

Research Program(s):

1. 314 - Tumor immunology (POF3-314) (POF3-314)

Appears in the scientific report 2020

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