UC San Diego

Chronic inflammation has long been recognized as a driving factor for cancer, including lung cancer. However, the specific inflammatory cells and pathways involved in supporting tumor growth remain poorly understood. Here, we studied the effect ofdigoxin, an inhibitor of the Retinoic Acid Receptor-Related Orphan Receptor Gamma and Gamma t (RORγ/γt) transcription factors, in two mouse models of lung cancer. We found that digoxin significantly reduced tumor growth in the KrasG12D model and the urethane-induced lung cancer model. Mechanically, digoxin decreased lung infiltration by RORγt+ CD4+ lymphocytes (Th17 cells) and the secretion of pro-inflammatory cytokines like interleukin 17A (IL-17A), IL-17F, and IL-22 by these cells in the tumor microenvironment (TME). Notably, digoxin showed no direct cytotoxicity on tumor cells, suggesting an indirect mechanism of action through inhibition of RORγt+ immune cells. Furthermore, we found in Rag1−/− mice that digoxin also inhibited RORγt+ innate immune cells, such as type 3 innate lymphoid cells (ILC3s) and natural killer 17 (NK17) cells. In conclusion, our study suggests that inhibiting RORγt can reshape the TME by decreasing pro-tumor inflammation; therefore, providing a potential target for future cancer therapies.