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

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.