The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The NRF2/KEAP1 pathway is crucial for cellular homeostasis and cancer prevention.
• Constitutive NRF2 activity in 30% of lung tumors promotes cancer survival and chemoresistance.
• The role of NRF2 in immune cells within the tumor microenvironment remains largely unexplored.

Purpose of the Study:

• To investigate the impact of NRF2 activation on macrophage phenotype and function within the tumor microenvironment.
• To evaluate the therapeutic potential of the NRF2 activator CDDO-Methyl ester (CDDO-Me) in lung tumorigenesis.

Main Methods:

• Utilized Nrf2 wild-type (WT) and knockout (KO) tumor-educated bone marrow-derived macrophages (TE-BMDMs).
• Treated macrophages and A/J mice with CDDO-Me, a NRF2 activator.
• Assessed macrophage phenotype (M1/M2 markers) and tumor burden in mice.

Main Results:

• CDDO-Me reprogrammed WT macrophages from a tumor-promoting to a tumor-inhibiting phenotype (increased M1 markers, decreased VEGF, CCL2, CD206).
• No changes were observed in Nrf2 KO macrophages treated with CDDO-Me.
• CDDO-Me reduced tumor burden and improved pathological grade in WT mice, but not in Nrf2 KO mice.
• Nrf2 KO mice exhibited significantly higher tumor burden compared to WT mice, irrespective of CDDO-Me treatment.

Conclusions:

• NRF2 activation in macrophages promotes an anti-cancer phenotype.
• NRF2 deficiency exacerbates lung tumorigenesis.
• CDDO-Me demonstrates NRF2-dependent anti-tumor efficacy by modulating macrophage activity.