Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells.
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.



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. 17This article is highlighted in the In This Issue feature, p. 1.
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Nikolaos
N
Svoronos
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Alfredo
A
Perales-Puchalt
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Michael J
MJ
Allegrezza
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Melanie R
MR
Rutkowski
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Kyle K
KK
Payne
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Amelia J
AJ
Tesone
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Jenny M
JM
Nguyen
The Graduate School of Biomedical Sciences, The University of Texas Health Science Center, San Antonio, Texas.|Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, Texas.
Tyler J
TJ
Curiel
Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware.
Mark G
MG
Cadungog
Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Sunil
S
Singhal
Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Evgeniy B
EB
Eruslanov
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Paul
P
Zhang
Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Julia
J
Tchou
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
Rugang
R
Zhang
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania. Jose.Conejo-Garcia@moffitt.org.
Jose R
JR
Conejo-Garcia
D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019061:src-Family Kinases
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