PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice

Tobias Gutting; Christian A Weber; Philip Weidner; Frank Herweck; Sarah Henn; Teresa Friedrich; Shuiping Yin; Julia Kzhyshkowska; Timo Gaiser; Klaus-Peter Janssen; Wolfgang Reindl; Matthias P A Ebert; Elke Burgermeister

doi:10.1080/2162402X.2017.1423168

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice

Oncoimmunology. 2018 Feb 1;7(5):e1423168. doi: 10.1080/2162402X.2017.1423168. eCollection 2018.

Affiliations

¹ Dept. of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
² Dept. of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Dept. of Pathology, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁴ Dept. of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Abstract

To identify novel hubs for cancer immunotherapy, we generated C57BL/6J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant KRASG12V oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant KRASG12V mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased Il4 mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARγ in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.

Keywords: PPAR; RAS; colorectal cancer; macrophages.

Publication types

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

Grants and funding

This work was supported by the Deutsche Krebshilfe (111086), Deutsche Krebshilfe (108287), Deutsches Krebsforschungszentrum (Ca158 DKFZ-MOST), Government of Baden-Württemberg Germany (Biology of Frailty), Medical Faculty Mannheim University Heidelberg (TRAPS), Government of Baden-Württemberg Germany (ZOBEL) and Deutsche Forschungsgemeinschaft (DFG) (BU2285).