Abstract 5176: CDDO-methyl ester redirects macrophage polarization and reduces lung tumor burden in a Nrf2-dependent manner

Abstract

Abstract The cytoprotective Nrf2 pathway impacts immune cell function and has been proposed as a target for many inflammation-related diseases, but the effects of Nrf2 activation on immune cells in the cancer context are not well characterized. With Nrf2 activators under development and in clinical trials, it is critical to understand the influence of these drugs on cancer progression. While the anti-inflammatory nature of Nrf2 activation protects healthy cells from malignant transformation, cancer cells can utilize the pathway to promote resistance to anti-cancer drugs and increase tumor cell survival. Up to 30% of human lung adenocarcinomas acquire mutations in the Nrf2 pathway which result in constitutive activation. However, triterpenoids, including CDDO-methyl ester (CDDO-Me, also known as bardoxolone methyl), are potent pharmacological Nrf2 activators with demonstrated anti-cancer activity in preclinical models. Lung cancer is the leading cause of cancer-related mortality worldwide, and macrophages are the most common immune cell type in the lung tumor microenvironment. To investigate Nrf2 activation in macrophages in the context of lung cancer, bone marrow-derived macrophages (BMDMs) were isolated from wild type (WT) and Nrf2 knock out (KO) mice and cultured in conditioned media from lung cancer cells to produce a tumor-educated phenotype. The triterpenoid CDDO-Me had anti-inflammatory effects in BMDMs stimulated with the conventional cytokines IFN-γ and LPS. Conversely, CDDO-Me increased (p < 0.05) the M1 macrophage markers TNFα, IL-6, and MHC-II and decreased the M2 macrophage markers VEGF, CCL2, and CD206 in tumor-educated BMDMs in a Nrf2-dependent manner. The phenotypic changes were observed on transcription, protein, and surface marker levels. This context-dependent reversal of BMDM polarization suggests that Nrf2 activation has different outcomes in different environments. To test CDDO-Me in vivo, lung tumors were initiated with vinyl carbamate in A/J WT and Nrf2 KO mice, and animals were fed either control diet or CDDO-Me (12.5-50 mg/kg of diet) for 16 weeks. CDDO-Me significantly (p < 0.05) decreased tumor number, size, and overall burden and reduced the histopathological severity of tumors in a Nrf2- and dose-dependent manner. Additionally, CDDO-Me increased the infiltration of CD64+ macrophages but decreased CD206+ expression in macrophages in the lungs of WT tumor-bearing mice. Interestingly, CD206 expression was higher on macrophages in the spleen of WT mice treated with CDDO-Me, suggesting a cancer context dependency. Future studies will evaluate the dependency of Nrf2 activation in macrophages for the anti-tumor activity of CDDO-Me. Citation Format: Jess Ann Moerland, Karen T. Liby. CDDO-methyl ester redirects macrophage polarization and reduces lung tumor burden in a Nrf2-dependent manner. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5176.