Estrogen receptor α signaling inhibits T cell responses against gynecologic tumors (TUM7P.943)

Abstract

Abstract Estradiol is a pleiotropic steroid hormone that regulates homeostasis, cell growth, and the immune system. In estrogen receptor positive breast cancer, anti-estrogen therapies are used to inhibit tumor cell growth. However, estrogen receptor α is also found on non-tumor cells within the tumor microenvironment. Therefore, we hypothesized that estradiol is able to affect tumor progression independent of its direct effect on tumor cells by regulating the tumor microenvironment, specifically immune cells. Using an orthotopic mouse model for ovarian cancer, we show that even in an estrogen receptor negative tumor, estradiol is able to drive tumor progression. Conversely, dependent upon an adaptive immune response, depletion of estrogen impedes tumor growth, as WT but not recombinase activating gene KO (RAG KO) estrogen-depleted mice survive longer than control littermates. This effect is dependent on estrogen receptor α expression in T cells. Mice reconstituted with a 1:1 mixture of WT and estrogen receptor α KO bone marrow reveal that estrogen receptor α KO T cells exhibit greater antitumor effector functions and pro-inflammatory cytokine production in a cell-intrinsic manner. These findings suggest anti-estrogens as a novel adjuvant therapy to augment T cell-dependent immunotherapies, such as adoptive cell transfer and programmed cell death protein 1 (PD-1) inhibition.