MON-315 Transcription Factor NRF2 May Serve as a Master Regulator of Immune Modulation and Lung Cancer Progression

Lung cancer contributes to the highest rates of cancer-related deaths world-wide. Approximately 80% of lung cancers are non-small cell lung cancers (NSCLC), and adenocarcino­mas (adenoCa) comprise about half of these. Importantly, >20% of lung adenoCa harbor mutations in transcription factor NRF2 and its inhibitor KEAP1 that promote NRF2 activation. Lung cancers with increased NRF2 levels are highly aggressive and have a poor prognosis. However, the mechanisms where­by NRF2 promotes lung cancer growth and progression are poorly understood. NRF2, a ‘primary mediator of cellular adaptation to oxida­tive stress,’ binds to promoters of anti-oxidant genes (e.g. HMOX1, NQO1), which have anti-inflammatory and immune modulatory activity. Hypothesis: NRF2 serves a crucial role in lung cancer progression by enhancing pro­duction of key immune mod­ulators that promotes immunosuppression and tumor progression. Objectives: To assess the roles of NRF2 on cAMP regulation of immune modulator expression in primary cultures of human fetal lung (HFL) epithelial cells and in human adenoCa cell lines Results: Using primary cultures of HFL epithelial cells and the human adenoCa cell lines, HCC4150 and H2347 (obtained from Dr. John Minna), we made the intri­guing discovery that cAMP markedly and coordinately induced expression of NRF2, its co-regu­lated transcriptional targets, C/EBPβ and PPARγ, the immune mod­u­la­tors, surfactant protein-A, HMOX1, GDF15, PD-L1 and TDO2, which catalyzes metab­olism of trypto­phan to kynurenine, and the kynurenine receptor, AhR. Furthermore, siRNA-mediated NRF2 knockdown inhibited C/EBPβ and PPARγ induction and blocked cAMP induction of immune modulators in both the HFL epithelial cells and adenoCa cell lines. ChIP-qPCR revealed that cAMP-induced binding of endogenous NRF2 to the promoters of all of these genes. Importantly, lung adenoCa with signatures of increased NRF2 activation manifest reduced immune cell infiltration, suggesting that NRF2 may create a more permissive immune environment. Accordingly, all of these immune modulators are known to promote survival of tumor metas­tases. Previous studies on triple-negative breast cancer cells indicated that the TDO2-AhR signaling axis mediated anoikis resistance, proliferation, migration, and invasion in culture, as well as increased metastatic capacity of xenografts in mice. Conclusions: Collectively our findings suggest that NRF2, acting with C/EBPβ and PPARγ, may serve a crucial role in lung cancer progression by enhancing pro­duction of key immune mod­ulators that promote tumor progression. We anticipate that our studies will reveal other NRF2-regulated pathways in NSCLC pathogenesis that will lead to develop­ment of novel and effective strategies for treating this devastating disease.