Interplay between Estrogen and Stat3/NF-κB Driven Immunomodulation in Lung Cancer.

K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3(Delta/Delta) mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-kappa B)-driven pro-tumor immune response while reducing tumorigenesis and enhancing antitumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-kappa B signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3(Delta/Delta )females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-kappa B-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-kappa B-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-kappa B activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3(Delta/Delta) males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-kappa B-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.