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Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

Heat Shock Protein-90 Inhibition Alters Activation of Pancreatic Stellate Cells and Enhances the Efficacy of PD-1 Blockade in Pancreatic Cancer

Yuchen Zhang, Michael B. Ware, Mohammad Y. Zaidi, Amanda N. Ruggieri, Brian M. Olson, Hannah Komar, Matthew R. Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M. Sarmiento, Rafi Ahmed, Shishir K. Maithel, Bassel F. El-Rayes and Gregory B. Lesinski
Yuchen Zhang
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
2Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China.
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Michael B. Ware
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Mohammad Y. Zaidi
3Department of Surgery, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Amanda N. Ruggieri
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Brian M. Olson
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Hannah Komar
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Matthew R. Farren
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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  • ORCID record for Matthew R. Farren
Ganji Purnachandra Nagaraju
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Chao Zhang
4Department of Biostatistics, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Zhengjia Chen
5Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, Illinois.
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Juan M. Sarmiento
3Department of Surgery, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Rafi Ahmed
6Emory Vaccine Center, Atlanta, Georgia.
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Shishir K. Maithel
3Department of Surgery, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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Bassel F. El-Rayes
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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  • For correspondence: gregory.b.lesinski@emory.edu bassel.el-rayes@emoryhealthcare.org
Gregory B. Lesinski
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
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  • For correspondence: gregory.b.lesinski@emory.edu bassel.el-rayes@emoryhealthcare.org
DOI: 10.1158/1535-7163.MCT-19-0911 Published January 2021
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

This article is featured in Highlights of This Issue, p. 1

Footnotes

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

  • Mol Cancer Ther 2021;20:150–60

  • Received September 19, 2019.
  • Revision received April 9, 2020.
  • Accepted September 30, 2020.
  • Published first October 9, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (1)
January 2021
Volume 20, Issue 1
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Heat Shock Protein-90 Inhibition Alters Activation of Pancreatic Stellate Cells and Enhances the Efficacy of PD-1 Blockade in Pancreatic Cancer
Yuchen Zhang, Michael B. Ware, Mohammad Y. Zaidi, Amanda N. Ruggieri, Brian M. Olson, Hannah Komar, Matthew R. Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M. Sarmiento, Rafi Ahmed, Shishir K. Maithel, Bassel F. El-Rayes and Gregory B. Lesinski
Mol Cancer Ther January 1 2021 (20) (1) 150-160; DOI: 10.1158/1535-7163.MCT-19-0911

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Heat Shock Protein-90 Inhibition Alters Activation of Pancreatic Stellate Cells and Enhances the Efficacy of PD-1 Blockade in Pancreatic Cancer
Yuchen Zhang, Michael B. Ware, Mohammad Y. Zaidi, Amanda N. Ruggieri, Brian M. Olson, Hannah Komar, Matthew R. Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M. Sarmiento, Rafi Ahmed, Shishir K. Maithel, Bassel F. El-Rayes and Gregory B. Lesinski
Mol Cancer Ther January 1 2021 (20) (1) 150-160; DOI: 10.1158/1535-7163.MCT-19-0911
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