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Lung adenocarcinomas (LUADs) with mutations in the  K-ras  oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of  K-ras  mutant LUAD are poorly understood. Here, we develop a lung epithelial specific  K-ras  mutant/ Stat3  conditional knockout (LR/ Stat3  Δ/Δ ) mouse model. Epithelial  Stat3  deletion results in intriguing sex-associated discrepancies;  K-ras  mutant tumors are decreased in female LR/ Stat3  Δ/Δ  mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following  Stat3  deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/ Stat3  Δ/Δ  mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments  K-ras  mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial  Stat3  signaling in  K-ras  mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer