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Research Article

Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF-β Inhibitor Sequencing in Melanoma

Fei Zhao, Kathy S Evans, Christine Xiao, Nicholas DeVito, Balamayooran Theivanthiran, Alisha Holtzhausen, Peter J. Siska, Gerard C Blobe and Brent A. Hanks
Fei Zhao
NIEHS/IIDL, NIH
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Kathy S Evans
Internal Medicine/Medical Oncology, Duke University Medical Center
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Christine Xiao
Internal Medicine/Medical Oncology, Duke University Medical Center
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Nicholas DeVito
Medicine, Duke University Medical Center
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Balamayooran Theivanthiran
Internal Medicine/Medical Oncology, Duke University Medical Center
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Alisha Holtzhausen
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
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  • ORCID record for Alisha Holtzhausen
Peter J. Siska
Internal Medicine III, University Hospital Regensburg
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Gerard C Blobe
Pharmacology & Cancer Biology, Duke University Medical Center
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Brent A. Hanks
Internal Medicine/Medical Oncology and Pharmacology/Cancer Biology, Duke University Medical Center
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  • ORCID record for Brent A. Hanks
  • For correspondence: hanks004@mc.duke.edu
DOI: 10.1158/2326-6066.CIR-18-0086
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Abstract

Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacological inhibition of the TGF-β signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAF(V600E) melanoma. Additional mechanistic studies revealed that TGF-β pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby, facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGF-β signaling activity. Delayed TGF-β inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGF-β inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGF-β inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance.

  • Received February 14, 2018.
  • Revision received June 1, 2018.
  • Accepted September 7, 2018.
  • Copyright ©2018, American Association for Cancer Research.

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Published OnlineFirst September 12, 2018
doi: 10.1158/2326-6066.CIR-18-0086

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Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF-β Inhibitor Sequencing in Melanoma
Fei Zhao, Kathy S Evans, Christine Xiao, Nicholas DeVito, Balamayooran Theivanthiran, Alisha Holtzhausen, Peter J. Siska, Gerard C Blobe and Brent A. Hanks
Cancer Immunol Res September 12 2018 DOI: 10.1158/2326-6066.CIR-18-0086

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Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF-β Inhibitor Sequencing in Melanoma
Fei Zhao, Kathy S Evans, Christine Xiao, Nicholas DeVito, Balamayooran Theivanthiran, Alisha Holtzhausen, Peter J. Siska, Gerard C Blobe and Brent A. Hanks
Cancer Immunol Res September 12 2018 DOI: 10.1158/2326-6066.CIR-18-0086
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