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

Daniel Baumann,Michael Volkmar,Corinna Schumacher,Sophie Luise Boos,Caroline Vent,Jennifer Drebant,Rienk Offringa,Irena Nickel,Oliver Strobel,Julian Mochayedi,Sven Blobner,Susann Wendler,Aline Sophie Daniel,Julia Han Noll,Tanja Hägele

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.

Highlights

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade
Benchmarking of the IC50 values against data available from literature led to the selection of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors (MEKi) GDC-0973, GDC-0623, as well as PI3K inhibitors (PI3Ki)
We focused our further experiments on MEKi GDC-0623, because we obtained most consistent in vitro efficacy data for this compound for the three tumor cell lines of interest (Fig. 1b)

Summary

Introduction

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. The underlying idea of this treatment concept is that tumor cell killing results in ‘immunogenic tumor cell death’, involving tumor antigen release and cell death-related pro-inflammatory signals, causing the recruitment of antigen presenting cells (APCs) including DCs into the tumor, followed by the uptake and processing of tumor antigens into MHC12 In this context, stimulation of DCs through their CD40 receptor provides an ‘adjuvant’ signal, causing the antigen-loaded DCs to migrate to the tumor-draining lymph nodes[13,14,15], as well as to convert them into fully mature DCs expressing high levels of MHC-restricted tumor antigen in the context of multiple T cell co-stimulatory signals[9]

Methods

Results

Conclusion