The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner
Jessica A. Moerland,
Ana S. Leal,
Beth Lockwood,
Elena Y. Demireva,
Huirong Xie,
Teresa Krieger-Burke,
Karen T. Liby
Affiliations
Jessica A. Moerland
Department of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USA
Ana S. Leal
Department of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USA
Beth Lockwood
Department of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USA
Elena Y. Demireva
Transgenic and Genome Editing Facility, Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USA
Huirong Xie
Transgenic and Genome Editing Facility, Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USA
Teresa Krieger-Burke
In Vivo Core Facility, Michigan State University, East Lansing, MI 48824, USA
Karen T. Liby
Department of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USA
The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (p p p p < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype.
