Abstract 1797: Impact of estrogen depletion using an aromatase inhibitor (AI) on EGFR-mutated non-small cell lung cancer (NSCLC) in a murine model
Authors: Bodor J. Nicholas , Macedo Rodrigo T. , Harvey Kristen , Vanderveer Lisa A. , Krzizike Daniel D. , Edelman Martin J. , Treat Joseph , Clapper Margie L. 
Published: April 2023

Abstract
EGFR-mutated lung tumors respond poorly to checkpoint (PD-1/PD-L1) inhibitors. Resistance to such therapies has been attributed to the prototypic immunosuppressed “cold” tumor microenvironment (TME) of EGFR-mutated NSCLCs, which is characterized by low levels of tumor infiltrating lymphocytes. Growing evidence from breast cancer studies demonstrates the ability of 17β-estradiol to regulate several species of immune cells within an immunosuppressive TME. Furthermore, treatment of breast cancers with AIs or estrogen receptor antagonists promotes lymphocyte infiltration and enhances immune reactivity. While the role of estrogen species in lung tumorigenesis is well documented, little attention has been given to their contribution to the immunosuppressed lung TME or the use of estrogen-modulating agents to attenuate these effects. The goal of this study was to evaluate the impact of estrogen depletion, using the AI exemestane (Exe), on levels of tumor infiltrating immune cells and other tumor endpoints in the murine model of mutated EGFRL858R NSCLC. Male (n = 42) and female (n = 39) mutEGFRL858R mice were gonadectomized at 6 weeks of age and doxycycline-supplemented chow was given to induce lung tumor development. Daily treatment with Exe (250 μg/kg) or vehicle was initiated at 8 weeks of age, and continued for the duration of the experiment (7 weeks). Body weights were recorded twice per week. At the time of euthanasia, lung tissues were processed for histopathological analysis and assessment of tumor CD8+ lymphocyte concentrations by immunohistochemistry was performed. Lung tumors from Exe-treated mice exhibited higher concentrations (median, Q1 - Q3) of CD8+ T cells per 20x field (77.5, 60.3 - 114.0) vs. those of vehicle-treated controls (61.0, 48.8 - 80.8) (P = 0.035). A trend of a decreased incidence of solid adenocarcinoma lesions within the lungs of Exe-treated vs. vehicle-treated control mice was observed in both males (26.3% vs. 38.1%) and females (26.3% vs. 35.0%). Among females, the incidence of continuous weight loss (over 3 consecutive weeks) was lower among Exe-treated (16.7%) vs. vehicle-treated (40.0%) mice. Early findings suggest that administration of AI therapy to mutEGFRL858R mice stimulates CD8+ lymphocyte infiltration within lung tumors, and inhibits both the formation of lung adenocarcinomas and disease-associated weight loss. Murine studies to further optimize the dose and schedule of AI treatment, as well as evaluate the ability of AI therapy to enhance the activity of checkpoint inhibitors in mutated EGFRL858R NSCLC are underway. (Supported by an In Vino Vita Award from Fox Chase Cancer Center and a R01 CA217161 from the NCI/NIH.)
Citation Format: J. Nicholas Bodor, Rodrigo T. Macedo, Kristen Harvey, Lisa A. Vanderveer, Daniel D. Krzizike, Martin J. Edelman, Joseph Treat, Margie L. Clapper. Impact of estrogen depletion using an aromatase inhibitor (AI) on EGFR-mutated non-small cell lung cancer (NSCLC) in a murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1797.