Estrogen Receptor α (ERα) Signaling and Tumor Cell-Derived Factors Mediate Pro-Tumor Neutrophil Activation in the Setting of Lymphangioleiomyomatosis (LAM) 2809

Abstract Description Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease associated with cystic tumor formation in the lungs caused by small smooth muscle tumors. LAM exclusively affects biological females; however, the origin of tumors is unknown. Our lab has utilized a conditional tuberous sclerosis-2 (Tsc2) knockout genetic mouse model of LAM to identify a possible myometrial origin of tumors. LAM has been shown to be estrogen-sensitive; however, LAM tumor cell lines respond poorly to estradiol in vitro. In tumors from our LAM mice, bulk RNA sequencing identified increased transcription of neutrophil elastase in response to estrogen stimulation. Previously our lab demonstrated that neutrophils are the primary infiltrate in the mouse LAM tumors, while neutrophil depletion has been shown to reduce tumor growth. Recent work suggests that estradiol signaling promotes neutrophil production via estrogen receptor α (ERα) signaling in the bone marrow. We hypothesize that estradiol, in concert with tumor-derived factors, may augment pro-tumorigenic functions of neutrophils in the setting of LAM. Neutrophils from ERα knockout mice vs. C57BL/6 control bone marrow cultured with tumor-conditioned media (TCM) demonstrated decreased expression of neutrophil activation markers including Elane, Nos2, and Pdl1. Future experiments involving neutrophil function and activation will further elucidate the relationship between estradiol and neutrophils in LAM. Funding Sources DOD TS220024, NIH R01HL168407 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)