Abstract ES10-3: Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis
Conejo-Garcia, J
Published in: Cancer Research
Although the role of estrogen signaling in the progression of a subset of breast tumors has been underscored by the clinical use of Estrogen Receptor antagonists, how estrogens impact protective anti-tumor immunity remains poorly investigated. Here we show that estrogen signaling accelerates the progression of different estrogen insensitive tumor models by contributing to tumor-promoting emergency myelopoiesis. This results in increased mobilization of myeloid-derived suppressor cells (MDSCs), and also increases their intrinsic immunosuppressive activity on a per cell basis, in vivo in the bone marrow of tumor-bearing hosts. Accordingly, estrogens have a profound effect on T-cell-dependent anti-tumor immunity and tumor-promoting inflammation, even 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 anti-tumor 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, selective antagonists of estrogen receptor alpha (but not estrogen receptor beta) could have significant effects in delaying the progression of estrogen-sensitive and estrogen-insensitive tumors, providing a rationale for blocking estrogen signals to boost the effectiveness of anti-cancer immunotherapies. Our data therefore provide novel mechanistic insight into how enhanced estrogenic activity contributes to malignant progression in established tumors by driving pathological, tumor-promoting myelopoiesis. Our work suggests that new anti-estrogen drugs without 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: Conejo-Garcia J. Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES10-3.
