Synthetic Oleanane Triterpenoids Reduce Tumor Growth and Promote an Anti-Tumor Immune Response Independent of Cancer KEAP1 Mutational Status

KEAP1 negatively regulates the cytoprotective factor NRF2 and is commonly inactivated in lung cancer cells. Loss-of-function <i>KEAP1</i> 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 <i>KEAP1</i> status. As <i>KEAP1</i>-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 <i>KEAP1</i>-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 <i>KEAP1</i> KO compared to WT cancer-conditioned media had enhanced tumor-promoting phenotypes, which reversed with CDDO-Me treatment. Similarly, subcutaneous <i>KEAP1</i> 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 <i>KEAP1</i> mutational status.