Baumann et al. selected a small molecule MEK (MAPK kinase) inhibitor which, when combined in vivo with CD40 agonism (but not anti-PD-1), promoted T cell priming/cytotoxicity, and controlled tumor growth in syngeneic mouse models, particularly in a pancreatic tumor model. MEK inhibition induced IFNγ/TNFα, promoted MHC antigen presentation, and inhibited Tregs, MDSCs, and M2 TAMs; anti-CD40 promoted costimulation, antigen presentation, CD4+/CD8+ T cell stimulation, and M1 TAMs. Transcriptomes of whole tumors from co-treated mice showed inhibition of cell cycle and biosynthesis, and incitement of pro-inflammatory pathways.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. Department of Surgery, He
Author Info: (1) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (2) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (3) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (4) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (5) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (6) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (7) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (8) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (9) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (10) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. Department of Oncogenic signaling pathways of colorectal/pancreatic cancer, Ludwig-Maximilians-Universitaet, Munich, Bavaria, 80539, Germany. (11) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (12) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (13) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (14) Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. (15) Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany. r.offringa@dkfz.de. Department of Surgery, Heidelberg University Hospital, Heidelberg, Baden-Wuerttemberg, 69120, Germany. r.offringa@dkfz.de.
