Abstract 2356: Estrogen medicates sex specific function of epithelial STAT3 in K-ras mutant lung tumorigenesis by reprogramming lung tumor microenvironment

Abstract

Activating mutations of K-ras are one of the most common molecular alterations associated with lung cancer but have not yielded to therapeutic attack so far. We have recently shown a sex-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant lung cancer. We specifically found that deletion of STAT3 in K-ras mutant lung epithelial cells (LR/STAT3 Δ/Δ mice) significantly reduced lung tumor burden in female mice which was associated with an enhanced anti-tumor immune response but, surprisingly, caused a dramatic enhancement of lung tumorigenesis and induction of a NF-κB driven pro-tumor immune response in male mice. To further dissect the mechanism of STAT3 dependent sex disparity in the pathogenies of K-ras mutant lung cancer, we performed loss- and gain- of function studies to manipulate estrogen signaling in both female and male mice. In LR/Stat3 Δ/Δ males, implantation of estrogen pellet led to significantly reduced lung tumor burden and decreased neutrophils in the lung. This was accompanied by decreased Il6, and Cxcl1 expression explaining reduced neutrophil numbers. We also detected reduced expression of immunosuppressive markers; Arg1, Nos2, Tgfb, Il10, indicating to an attenuated immunosuppressive pro-tumor microenvironment. On the other hand, bilateral oophorectomy in female LR/Stat3 Δ/Δ mice led to higher tumor burden, higher lung neutrophil counts, and increased Il6, and Cxcl1 expression. We also found decreased expression of Gzmb, and Ifng, and increased expression of T regulatory markers Foxp3 and Il10, suggesting an attenuated cytotoxic immune response but a stronger immune-inhibitory response. Hormonal replacement therapy by implanting estrogen pellet in oophorectomized LR/Stat3 Δ/Δ females rescued the tumor-promoting effect of estrogen depletion characterized by reduced tumor number and neutrophil infiltration, decreased expression of Il6, Cxcl1, Foxp3 and Il10, and increased Gzmb and Ifng expression. Taken together, our study suggests that there is a differential regulation of NF-κB activation in K-ras mutant lung epithelium within sex, and estrogen plays a protective role (anti-tumor) by suppressing the activation of NF-κB pathway and reformatting the lung tumor microenvironment toward an anti-tumor phenotype. Our finding could lead to development of personalized (e.g. sex-based) immunotherapeutic and/or preventive modalities for K-ras mutant lung cancer. Citation Format: Shanshan Deng, Marco Ramos-Castaneda, Walter Velasco Torrez, Oscar Noble, Neha Daga, Mauricio Caetano, Seyed Javad Moghaddam. Estrogen medicates sex specific function of epithelial STAT3 in K-ras mutant lung tumorigenesis by reprogramming lung tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2356.