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Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner

Defne Bayik, Yadi Zhou, Chihyun Park, Changjin Hong, Daniel Vail, Daniel J. Silver, Adam Lauko, Gustavo Roversi, Dionysios C. Watson, Alice Lo, Tyler J. Alban, Mary McGraw, Mia Sorensen, Matthew M. Grabowski, Balint Otvos, Michael A. Vogelbaum, Craig Horbinski, Bjarne Winther Kristensen, Ahmad M. Khalil, Tae Hyun Hwang, Manmeet S. Ahluwalia, Feixiong Cheng and Justin D. Lathia
Defne Bayik
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Cleveland, Ohio.
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  • ORCID record for Defne Bayik
Yadi Zhou
3Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
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Chihyun Park
4Quantitative Health Science, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
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Changjin Hong
4Quantitative Health Science, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
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Daniel Vail
5Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
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Daniel J. Silver
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Cleveland, Ohio.
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Adam Lauko
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
6Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio.
7Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
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Gustavo Roversi
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
6Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio.
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Dionysios C. Watson
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Cleveland, Ohio.
8University Hospitals Cleveland Medical Center, Cleveland, Ohio.
9School of Medicine, Case Western Reserve University, Cleveland, Ohio.
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  • ORCID record for Dionysios C. Watson
Alice Lo
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
10Case Western Reserve University, Cleveland, Ohio.
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Tyler J. Alban
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Cleveland, Ohio.
11Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio.
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Mary McGraw
12Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
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Mia Sorensen
13Department of Pathology, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Matthew M. Grabowski
12Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
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  • ORCID record for Matthew M. Grabowski
Balint Otvos
12Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
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Michael A. Vogelbaum
14Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida.
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Craig Horbinski
15Department of Pathology and Neurosurgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
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Bjarne Winther Kristensen
13Department of Pathology, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Ahmad M. Khalil
2Case Comprehensive Cancer Center, Cleveland, Ohio.
5Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
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Tae Hyun Hwang
2Case Comprehensive Cancer Center, Cleveland, Ohio.
4Quantitative Health Science, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
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Manmeet S. Ahluwalia
2Case Comprehensive Cancer Center, Cleveland, Ohio.
12Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
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Feixiong Cheng
2Case Comprehensive Cancer Center, Cleveland, Ohio.
3Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
11Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio.
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Justin D. Lathia
1Cancer Impact Area and Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Cleveland, Ohio.
12Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
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  • For correspondence: lathiaj@ccf.org
DOI: 10.1158/2159-8290.CD-19-1355 Published August 2020
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Abstract

Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM.

Significance: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.

See related commentary by Gabrilovich et al., p. 1100.

This article is highlighted in the In This Issue feature, p. 1079

Footnotes

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

  • Cancer Discov 2020;10:1210–25

  • Received November 20, 2019.
  • Revision received February 29, 2020.
  • Accepted April 13, 2020.
  • Published first April 16, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (8)
August 2020
Volume 10, Issue 8
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Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner
Defne Bayik, Yadi Zhou, Chihyun Park, Changjin Hong, Daniel Vail, Daniel J. Silver, Adam Lauko, Gustavo Roversi, Dionysios C. Watson, Alice Lo, Tyler J. Alban, Mary McGraw, Mia Sorensen, Matthew M. Grabowski, Balint Otvos, Michael A. Vogelbaum, Craig Horbinski, Bjarne Winther Kristensen, Ahmad M. Khalil, Tae Hyun Hwang, Manmeet S. Ahluwalia, Feixiong Cheng and Justin D. Lathia
Cancer Discov August 1 2020 (10) (8) 1210-1225; DOI: 10.1158/2159-8290.CD-19-1355

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Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner
Defne Bayik, Yadi Zhou, Chihyun Park, Changjin Hong, Daniel Vail, Daniel J. Silver, Adam Lauko, Gustavo Roversi, Dionysios C. Watson, Alice Lo, Tyler J. Alban, Mary McGraw, Mia Sorensen, Matthew M. Grabowski, Balint Otvos, Michael A. Vogelbaum, Craig Horbinski, Bjarne Winther Kristensen, Ahmad M. Khalil, Tae Hyun Hwang, Manmeet S. Ahluwalia, Feixiong Cheng and Justin D. Lathia
Cancer Discov August 1 2020 (10) (8) 1210-1225; DOI: 10.1158/2159-8290.CD-19-1355
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