Abstract B06: 17β-estradiol negatively regulates natural killer cells and promotes breast cancer metastasis
Authors: Byemerwa Jovita K , Goyal Aditi , Artham Sandeep , Haines Corinne , Chang Chingyi , McDonnell Donald 
Published: December 2022

Abstract
Breast cancer metastasis accounts for 90% of breast cancer mortality highlighting the need for new therapeutic interventions that can be used in the treatment of advanced disease. Interesting in this regard is the successful development of approaches to increase tumor immunity in several solid tumors although, as yet, these interventions have only been impactful in a small subset of breast cancer patients. Whilst it has been established outside the realm of cancer that sex steroid hormones, especially estrogens, are key regulators of immunological responses, little is known about how these hormones affect immunological responses in the context of breast cancer. It is significant, therefore, that we have demonstrated that estrogen receptor-alpha (ER-α), the major intracellular mediator of responses to estrogens, is expressed in several different immune cells in the tumor microenvironment. How this receptor can be targeted to increase tumor immunity is a major focus of our current research efforts. For this study we utilized estrogen-non-responsive breast cancer cell lines allowing us to evaluate the roles of cancer cell extrinsically expressed ERα on metastasis. Mice were ovariectomized and supplemented with either placebo or an estrogen, 17β-estradiol (E2) in drinking water. Luciferase-labelled breast cancer cells were injected intravenously through the tail vein (for experimental metastasis) or into the mammary fat pad (for spontaneous metastasis) into syngeneic hosts. Metastasis burden was quantified using bioluminescence imaging and flow cytometry was utilized to assess changes in immune cell repertoire and activity. Analogous experiments were also performed in immunocompromised NOD-scid IL2Rgammanull (NSG) mice to assess the specific contribution of immune cells to the phenotypes observed. Interestingly, E2 supplementation in immunocompromised NSG mice led to decreased metastasis of breast cancer cells to the lungs, while the same treatment in immunocompetent C57BL/6 mice resulted in increased metastasis. These findings indicated that E2 negatively impacts anti-tumor immunity in immunocompetent hosts to promote metastasis. Immunoprofiling revealed that E2 decreased natural killer (NK) cell numbers, activation status, and their ability to produce IFNg. Additionally, genetic knockout of ERα specifically in NK cells led to increased NK cell numbers in the lung, increased production of IFNg from NK cells, and decreased metastatic burden. In-vitro, E2 decreased the production of IFNg in a dose-dependent manner in NK-cells and reduced their cytotoxicity against MHC-I low cells. Altogether, these results indicate that targeting the E2-ERα signaling axis in NK cells might be beneficial in the setting of metastatic breast cancer. Our ongoing studies are exploring how mechanistically distinct ERα modulators regulate NK cell activity with a view to developing new approaches to increase breast tumor immunity.
Citation Format: Jovita K Byemerwa, Aditi Goyal, Sandeep Artham, Corinne Haines, Chingyi Chang, Donald McDonnell. 17β-estradiol negatively regulates natural killer cells and promotes breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B06.