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Cancer Immunology Research
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Research Articles

Dysregulated NF-κB–Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma

Deena M. Maurer, Juraj Adamik, Patricia M. Santos, Jian Shi, Michael R. Shurin, John M. Kirkwood, Walter J. Storkus and Lisa H. Butterfield
Deena M. Maurer
1Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Juraj Adamik
2Parker Institute for Cancer Immunotherapy, and University of California San Francisco, Microbiology and Immunology, San Francisco, California.
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  • ORCID record for Juraj Adamik
Patricia M. Santos
3UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Jian Shi
3UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Michael R. Shurin
4Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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John M. Kirkwood
3UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Walter J. Storkus
4Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
5Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania.
6Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Lisa H. Butterfield
2Parker Institute for Cancer Immunotherapy, and University of California San Francisco, Microbiology and Immunology, San Francisco, California.
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  • ORCID record for Lisa H. Butterfield
  • For correspondence: lbutterfield@parkerici.org
DOI: 10.1158/2326-6066.CIR-20-0274 Published December 2020
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Abstract

Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic but are rarely effective in promoting objective clinical responses. To identify critical molecules for activation of effective antitumor immunity, we have profiled autologous dendritic cell (DC) vaccines used to treat 35 patients with melanoma. We showed that checkpoint molecules induced by ex vivo maturation correlated with in vivo DC vaccine activity. Melanoma patient DCs had reduced expression of cell surface inducible T-cell costimulator ligand (ICOSL) and had defective intrinsic NF-κB signaling. Chromatin immunoprecipitation assays revealed NF-κB–dependent transcriptional regulation of ICOSL expression by DCs. Blockade of ICOSL on DCs reduced priming of antigen-specific CD8+ and CD4+ T cells from naïve donors in vitro. Concentration of extracellular/soluble ICOSL released from vaccine DCs positively correlated with patient clinical outcomes, which we showed to be partially regulated by ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-κB signaling, the regulation of matrix metalloproteinases, and DC-derived ICOSL in the specific priming of cognate T-cell responses in the cancer setting. This study supports the implementation of targeted strategies to augment these pathways for improved immunotherapeutic outcomes in patients with cancer.

Footnotes

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

  • Cancer Immunol Res 2020;8:1554–67

  • Received April 10, 2020.
  • Revision received July 2, 2020.
  • Accepted September 18, 2020.
  • Published first October 13, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (12)
December 2020
Volume 8, Issue 12
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Dysregulated NF-κB–Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma
Deena M. Maurer, Juraj Adamik, Patricia M. Santos, Jian Shi, Michael R. Shurin, John M. Kirkwood, Walter J. Storkus and Lisa H. Butterfield
Cancer Immunol Res December 1 2020 (8) (12) 1554-1567; DOI: 10.1158/2326-6066.CIR-20-0274

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Dysregulated NF-κB–Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma
Deena M. Maurer, Juraj Adamik, Patricia M. Santos, Jian Shi, Michael R. Shurin, John M. Kirkwood, Walter J. Storkus and Lisa H. Butterfield
Cancer Immunol Res December 1 2020 (8) (12) 1554-1567; DOI: 10.1158/2326-6066.CIR-20-0274
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