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/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (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 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-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.

Targeting IL-1ß as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer.

K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1ß, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1ß in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1ß using an anti-IL-1ß mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1ß blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1ß blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.