Abstract SY01-02: Blockade of estrogen signaling boosts antitumor immunity by dwindling cancer-promoting myelopoiesis

Abstract

Abstract Although the role of estrogen signaling in the progression of breast tumors and a subset of ovarian cancer patients has been underscored by the clinical use of ER antagonists, how estrogens impact the orchestration and maintenance of protective antitumor immunity remains elusive. Here we show that estrogen signaling accelerates the progression of different estrogen-insensitive tumor models by contributing to tumor-promoting, expanded myelopoiesis. This results in increased mobilization of myeloid-derived suppressor cells (MDSCs) and also the augmentation of their intrinsic immunosuppressive activity on a per cell basis, in vivo in the bone marrow of tumor-bearing hosts. Accordingly, estrogens had a profound effect on T cell-dependent antitumor immunity and tumor-promoting inflammation, independently of the sensitivity of tumor cells to estrogen signaling. Differences in tumor growth in the presence of estrogen-insensitive tumor cells are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and also upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Consequently, fulvestrant had significant effects in delaying the progression of estrogen-insensitive tumors, providing a rationale for blocking estrogen signals to boost the effectiveness of anticancer immunotherapies, which is currently being tested at our institution in breast cancer patients. Our data therefore provide novel mechanistic insight into how enhanced estrogenic activity contributes to malignant progression in established tumors by driving pathologic, tumor-promoting myelopoiesis. Our work suggests that new antiestrogen drugs that have no agonistic effects (different from tamoxifen) could have benefits to boost protective immunity in a wide range of cancers, while augmented estrogenic activity could contribute to tumor initiation and/or malignant progression. Citation Format: Nikolaos Svoronos, Alfredo Perales-Puchalt, Jose R. Conejo-Garcia. Blockade of estrogen signaling boosts antitumor immunity by dwindling cancer-promoting myelopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY01-02.