Deng S, et al. Carcinogenesis 2020.
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. Absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced an NF-κB driven pro-tumor immune
response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB driven immuno-suppressive response, and reduced anti-tumor cytotoxicity, while estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB driven immunosuppression, and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.