Abstract B05: Assessing estrogen receptor signaling and function in dendritic cells within the tumor microenvironment


 Significant differences exist in the incidence and severity of various inflammatory diseases between males and females. Further, sex hormones such as estrogens, through their ability to regulate both innate and adaptive immune responses, have been shown to impact the pathobiology of many diseases. Notwithstanding this knowledge, it is not clear how and to what extent ER signaling within immune cells impacts tumor immunity and if and how this can be exploited therapeutically. To address this question, we performed tumor growth studies using various murine estrogen (E2)-nonresponsive breast cancer cell lines. Female mice were ovariectomized to remove the endogenous source of estrogens, and in turn, supplemented with either placebo or slow-releasing E2 pellets. One week later, tumor cells were injected orthotopically and tumor volume measured every two to three days for 14 days. Despite being non-responsive in vitro, E2 administration accelerates the growth of these tumors in vivo, and this activity was ablated using ER-antagonists. To evaluate the contribution of immune cells in estrogen-biology in these tumors, we performed similar studies in NOD-scid IL2Rgammanull (NSG) mice, which lack functional innate and adaptive immune responses. E2 failed to increase tumor growth in these mice, implicating immune cells as mediators of E2 action on tumors. Immunoprofiling of syngeneic tumors revealed a robust and consistent reduction in the number of major histocompatibility complex (MHC) Class II-expressing cells in the tumor microenvironment of E2-treated mice. Single-cell RNA-sequencing of the tumors revealed that the most prevalent MHC-II-expressing cell impacted were dendritic cells. Flow cytometry analysis confirmed the downregulation of MHCII expression on dendritic cells and other myeloid cell populations isolated from E2-treated tumors. MHCII expression on the surface of dendritic cells is important for the presentation of tumor antigens to T cells the decrease of which may compromise anti-tumor immunity. Paradoxically, using bone-marrow derived dendritic cells it was observed that E2 treatment increased the expression of MHC Class II complex, but this positive response was ablated when cells were cultured in tumor-conditioned media. This result suggests that although estrogens have a positive impact on dendritic cell function under normal circumstances these are attenuated by tumor-produced factors. Our ongoing work is focused on a dissection of estrogen signaling in dendritic cells and an evaluation of the impact of mechanistically distinct modulators on these processes and how they influence tumor immunity.
 Citation Format: Felicia Lim, Corinne Haines, ChingYi Chang, Donald Mcdonnell. Assessing estrogen receptor signaling and function in dendritic cells within the tumor microenvironment [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 B05.