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; Rienk Offringa

doi:10.1038/s41467-020-15979-2

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

Nat Commun. 2020 May 1;11(1):2176. doi: 10.1038/s41467-020-15979-2.

Authors

Daniel Baumann^{1

2}, Tanja Hägele¹, Julian Mochayedi¹, Jennifer Drebant¹, Caroline Vent^{1

2}, Sven Blobner¹, Julia Han Noll¹, Irena Nickel¹, Corinna Schumacher¹, Sophie Luise Boos^{1

3}, Aline Sophie Daniel¹, Susann Wendler^{1

2}, Michael Volkmar^{1

2}, Oliver Strobel², Rienk Offringa^{4

5}

Affiliations

¹ Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany.
² Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany.
³ Department of Oncogenic signaling pathways of colorectal/pancreatic cancer, Ludwig-Maximilians-Universitaet, Munich, Bavaria, 80539, Germany.
⁴ Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. [email protected].
⁵ Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy*
Animals
Antibodies, Monoclonal / pharmacology*
Antibodies, Monoclonal / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / chemistry
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Biomarkers, Pharmacological / metabolism
CD40 Antigens / agonists*
CD40 Antigens / immunology
Carcinoma, Pancreatic Ductal / drug therapy*
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
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
T-Lymphocytes / drug effects
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Transcriptome / genetics

Substances

Antibodies, Monoclonal
Biomarkers, Pharmacological
CD40 Antigens
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase Kinases