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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 and Jose R. Conejo-Garcia
Nikolaos Svoronos
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Alfredo Perales-Puchalt
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Michael J. Allegrezza
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Melanie R. Rutkowski
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Kyle K. Payne
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Amelia J. Tesone
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Jenny M. Nguyen
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Tyler J. Curiel
2The Graduate School of Biomedical Sciences, The University of Texas Health Science Center, San Antonio, Texas.
3Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas.
4Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, Texas.
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Mark G. Cadungog
5Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware.
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Sunil Singhal
6Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
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Evgeniy B. Eruslanov
6Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
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Paul Zhang
7Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Julia Tchou
8Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
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Rugang Zhang
9Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Jose R. Conejo-Garcia
1Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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  • For correspondence: Jose.Conejo-Garcia@moffitt.org
DOI: 10.1158/2159-8290.CD-16-0502 Published January 2017
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Abstract

The role of estrogens in antitumor immunity remains poorly understood. Here, we show that estrogen signaling accelerates the progression of different estrogen-insensitive 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. Cancer Discov; 7(1); 72–85. ©2016 AACR.

See related commentary by Welte et al., p. 17.

This article is highlighted in the In This Issue feature, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received May 2, 2016.
  • Revision received September 28, 2016.
  • Accepted September 28, 2016.
  • ©2016 American Association for Cancer Research.
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Cancer Discovery: 7 (1)
January 2017
Volume 7, Issue 1
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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 and Jose R. Conejo-Garcia
Cancer Discov January 1 2017 (7) (1) 72-85; DOI: 10.1158/2159-8290.CD-16-0502

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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 and Jose R. Conejo-Garcia
Cancer Discov January 1 2017 (7) (1) 72-85; DOI: 10.1158/2159-8290.CD-16-0502
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