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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Polyamine Blocking Therapy Decreases Survival of Tumor-Infiltrating Immunosuppressive Myeloid Cells and Enhances the Antitumor Efficacy of PD-1 Blockade

Eric T. Alexander, Kelsey Mariner, Julia Donnelly, Otto Phanstiel IV and Susan K. Gilmour
Eric T. Alexander
1Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
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Kelsey Mariner
1Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
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Julia Donnelly
1Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
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Otto Phanstiel IV
2University of Central Florida, Department of Medical Education, College of Medicine, Orlando, Florida.
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Susan K. Gilmour
1Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
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  • For correspondence: gilmours@mlhs.org
DOI: 10.1158/1535-7163.MCT-19-1116 Published October 2020
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Abstract

Despite unprecedented advances in the treatment of cancer through the use of immune checkpoint blockade (ICB), responses are not universal and alternative strategies are needed to enhance responses to ICB. We have shown previously that a novel polyamine blocking therapy (PBT), consisting of cotreatment with α-difluoromethylornithine (DFMO) to block polyamine biosynthesis and a Trimer polyamine transport inhibitor, decreases myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM). Both MDSCs and TAMs promote tumor progression, inhibit antitumor immunity, and limit the efficacy of ICB. In this study, we investigated the use of PBT to heighten therapeutic responses to PD-1 blockade in mice bearing 4T1 mammary carcinoma and B16F10 melanoma tumors. Whereas PBT inhibited primary tumor growth in both tumor models, 4T1 lung metastases were also dramatically decreased in mice treated with PBT. Reductions in MDSC and TAM subpopulations in 4T1 tumors from PBT-treated mice were accompanied by reduced cytoprotective autophagy only in tumor-infiltrating MDSC and macrophage subpopulations but not in the lung or spleen. PBT treatment blunted M2-like alternative activation of bone marrow–derived macrophages and reduced STAT3 activation in MDSC cultures while increasing the differentiation of CD80+, CD11c+ macrophages. PBT significantly enhanced the antitumor efficacy of PD-1 blockade in both 4T1 and B16F10 tumors resistant to anti–PD-1 monotherapy, increasing tumor-specific cytotoxic T cells and survival of tumor-bearing animals beyond that with PBT or PD-1 blockade alone. Our results suggest that cotreatment with DFMO and the Trimer polyamine transport inhibitor may improve the therapeutic efficacy of immunotherapies in patients with cancer with resistant tumors.

Footnotes

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

  • Mol Cancer Ther 2020;19:2012–22

  • Received December 3, 2019.
  • Revision received May 12, 2020.
  • Accepted July 16, 2020.
  • Published first August 3, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (10)
October 2020
Volume 19, Issue 10
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Polyamine Blocking Therapy Decreases Survival of Tumor-Infiltrating Immunosuppressive Myeloid Cells and Enhances the Antitumor Efficacy of PD-1 Blockade
Eric T. Alexander, Kelsey Mariner, Julia Donnelly, Otto Phanstiel IV and Susan K. Gilmour
Mol Cancer Ther October 1 2020 (19) (10) 2012-2022; DOI: 10.1158/1535-7163.MCT-19-1116

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Polyamine Blocking Therapy Decreases Survival of Tumor-Infiltrating Immunosuppressive Myeloid Cells and Enhances the Antitumor Efficacy of PD-1 Blockade
Eric T. Alexander, Kelsey Mariner, Julia Donnelly, Otto Phanstiel IV and Susan K. Gilmour
Mol Cancer Ther October 1 2020 (19) (10) 2012-2022; DOI: 10.1158/1535-7163.MCT-19-1116
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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