Tumor cell–independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells

Nikolaos Svoronos, Alfredo Perales-Puchalt, Michael J. Allegrezza, Melanie R. Rutkowski, Kyle K. Payne, Amelia J. Tesone, Jenny M. Nguyen, Tyler J Curiel, Mark G. Cadungog, Sunil Singhal, Evgeniy B. Eruslanov, Paul Zhang, Julia Tchou, Rugang Zhang, Jose R. Conejo-Garcia

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57 Scopus citations

Abstract

The role of estrogens in antitumor immunity remains poorly understood. Here, we show that estrogen signaling accelerates the progression of different estrogeninsensitive tumor models by contributing to deregulated myelopoiesis by both driving the mobilization of myeloid-derived suppressor cells (MDSC) and enhancing their intrinsic immunosuppressive activity in vivo. Differences in tumor growth are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and 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. Therefore, estrogen signaling is a crucial mechanism underlying pathologic myelopoiesis in cancer. Our work suggests that new antiestrogen drugs that have no agonistic effects may have benefits in a wide range of cancers, independently of the expression of estrogen receptors in tumor cells, and may synergize with immunotherapies to significantly extend survival. SIGNIFICANCE: Ablating estrogenic activity delays malignant progression independently of the tumor cell responsiveness, owing to a decrease in the mobilization and immunosuppressive activity of MDSCs, which boosts T-cell–dependent antitumor immunity. Our results provide a mechanistic rationale to block estrogen signaling with newer antagonists to boost the effectiveness of anticancer immunotherapies.

Original languageEnglish (US)
Pages (from-to)72-85
Number of pages14
JournalCancer Discovery
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2017

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ASJC Scopus subject areas

  • Oncology

Cite this

Svoronos, N., Perales-Puchalt, A., Allegrezza, M. J., Rutkowski, M. R., Payne, K. K., Tesone, A. J., Nguyen, J. M., Curiel, T. J., Cadungog, M. G., Singhal, S., Eruslanov, E. B., Zhang, P., Tchou, J., Zhang, R., & Conejo-Garcia, J. R. (2017). Tumor cell–independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discovery, 7(1), 72-85. https://doi.org/10.1158/2159-8290.CD-16-0502