Related Experiment Video
Updated: Jan 7, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Synthetic Oleanane Triterpenoids Reduce Tumor Growth and Promote an Anti-Tumor Immune Response Independent of Cancer
Christopher J Occhiuto1, Jessica A Moerland2, Karen T Liby3
1Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Abstract:
KEAP1 negatively regulates the cytoprotective factor NRF2 and is commonly inactivated in lung cancer cells. Loss-of-function KEAP1 mutations in cancer cells contribute to NRF2 activation and tumor immune evasion through immunosuppression and drug resistance. Counterintuitively, treatment with synthetic oleanane triterpenoids, potent NRF2 activators, reduces the pre-clinical tumor burden. This suggests the functional target of these drugs in cancer models is not the cancer cells but another tumor immune microenvironment (TIME) cell population. The anti-tumor potential of cells within the TIME, particularly macrophages, is potentiated by triterpenoid treatment in cancers with wild-type KEAP1 status. As KEAP1-mutant cancers show reduced tumor immune responses, triterpenoid-mediated immune stimulation may particularly benefit these cases, but this has not been investigated. To characterize the immunomodulatory effects of triterpenoids in KEAP1-mutant lung cancer, we studied tumor-educated bone marrow-derived macrophages (TE-BMDMs) and lung cancer models treated with the triterpenoids CDDO-Me or omaveloxolone. RNA-sequencing of TE-BMDMs cultured in KEAP1 KO compared to WT cancer-conditioned media had enhanced tumor-promoting phenotypes, which reversed with CDDO-Me treatment. Similarly, subcutaneous KEAP1 KO tumors were larger and more immune-suppressed compared to WT tumors. Both CDDO-Me and omaveloxolone reduced the tumor burden and improved immune cell phenotypes within the TIME independent of KEAP1 mutational status.
Insights
Synthetic triterpenoids, NRF2 activators, reduce lung cancer burden by modulating the tumor immune microenvironment (TIME). These drugs enhance anti-tumor immunity in KEAP1-mutant cancers, independent of KEAP1 status.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- KEAP1 regulates NRF2; KEAP1 inactivation in lung cancer promotes immune evasion and drug resistance.
- Synthetic oleanane triterpenoids activate NRF2 and reduce tumor burden, suggesting a TIME target.
- Triterpenoids enhance anti-tumor immunity in wild-type KEAP1 cancers, but effects in KEAP1-mutant cancers are unknown.
Purpose of the Study:
- To investigate the immunomodulatory effects of triterpenoids in KEAP1-mutant lung cancer.
- To characterize triterpenoid effects on tumor-educated macrophages and lung cancer models.
- To determine if triterpenoid treatment benefits KEAP1-mutant lung cancers.
Main Methods:
- Studied tumor-educated bone marrow-derived macrophages (TE-BMDMs) and lung cancer models.
- Treated models with CDDO-Me or omaveloxolone, NRF2-activating triterpenoids.
- Utilized RNA-sequencing to analyze macrophage phenotypes and assessed tumor burden and TIME immune cell phenotypes.
Main Results:
- KEAP1 KO cancer-conditioned media enhanced tumor-promoting macrophage phenotypes, reversed by CDDO-Me.
- KEAP1 KO tumors were larger and more immune-suppressed than wild-type tumors.
- CDDO-Me and omaveloxolone reduced tumor burden and improved TIME immune cell phenotypes, irrespective of KEAP1 status.
Conclusions:
- Triterpenoid treatment reverses pro-tumorigenic macrophage phenotypes in KEAP1-mutant lung cancer models.
- These drugs reduce tumor burden and enhance anti-tumor immunity in KEAP1-mutant lung cancer.
- Triterpenoids offer therapeutic potential for lung cancer by modulating the tumor immune microenvironment, independent of KEAP1 mutational status.
More Related Videos
09:04Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
19:44Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
Published on: May 30, 2012
Related Concept Videos
01:27Tumor Immunotherapy
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:17The Tumor Microenvironment
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...