Abstract 2689: Targeting mesenchymal cells with epigenetic therapy in lung cancer and lung disease

Abstract Lung diseases, including fibrosis and cancer, are major health problems that together lead to millions of deaths each year. Non-small-cell lung cancer (NSCLC) has high morbidity and mortality rates, and patient prognosis and survival are very poor. Similarly, pulmonary fibrosis is a life-threatening respiratory disease characterized by scarring and damage caused by increased abundance of collagen-secreting myofibroblasts. An autopsy study showed that as many as one third of non-small cell lung cancer patients have some amount of pulmonary fibrosis1, suggesting that these two diseases frequently co-exist. Our laboratory has also found that higher abundance of mesenchymal cells in tumors predicts a poor prognosis2. Various literature has identified Enhancer of Zeste Homolog 2 (EZH2), which is responsible for mediating histone 3 lysine 27 trimethylation, as a key regulator of lung disease. Several EZH2 inhibitors (tazemetostat and valemetostat) provide a reliable and therapeutically tolerable treatment option for diseased patients. Our central hypothesis is that EZH2 inhibition can prevent or reverse fibrosis via targeting myofibroblasts. To test this hypothesis, we have established pulmonary mesenchymal cell lines from both normal and diseased human lung. We observed that EZH2 inhibition slowed cell proliferation with or without TGF-beta, a cytokine known to drive a myofibroblast fate. In vivo, we have observed that EZH2 inhibition attenuates the fibrosis that occurs after exposure to bleomycin. Next, we are testing the roles of these mesenchymal cells in responses to cancer therapies, including immunotherapy. For our initial experiments, we used murine pulmonary mesenchymal cells grown with tumor cells and immune cells in a 3-dimensional Matrigel co-cultures. This culture system mimics aspects of the tumor immune microenvironment in vitro and has allowed us to test therapies including EZH2 inhibition and anti-PD1 immunotherapy in a tractable system. Our preliminary results suggest that EZH2 inhibition can alter cells to be more susceptible to anti-PD1, and we are now examining the contributions of mesenchymal cells to these phenotypes. Together our results suggest that targeting EZH2 may improve aspects of both pulmonary fibrosis and lung cancer, and be a way to target these co-occurring diseases to improve patient outcomes. 1doi: 10.7196/ajtccm.2020.v26i1.050, 2 doi: 10.1016/j.labinv.2023.100176. Funded by R01 CA237643, R01 HL170193, and P30 CA177558 (Markey Shared Resources). Citation Format: Dave-Preston Esoe, Avery R. Childress, Xiulong Song, Jamie Sturgill, Christopher M. Waters, Christine F. Brainson. Targeting mesenchymal cells with epigenetic therapy in lung cancer and lung disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2689.