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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI180983

Parkin activates innate immunity and promotes anti-tumor immune responses

Michela Perego,1 Minjeong Yeon,1 Ekta Agarwal,1 Andrew T. Milcarek,1 Irene Bertolini,1 Chiara Camisaschi,3 Jagadish C. Ghosh,1 Hsin-Yao Tang,4 Nathalie Grandvaux,5 Marcus Ruscetti,6 Andrew V. Kossenkov,4 Sarah Preston-Alp,7 Italo Tempera,7 Noam Auslander,4 and Dario C. Altieri1

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Perego, M. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Yeon, M. in: JCI | PubMed | Google Scholar

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Agarwal, E. in: JCI | PubMed | Google Scholar

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Milcarek, A. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Bertolini, I. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Camisaschi, C. in: JCI | PubMed | Google Scholar

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Ghosh, J. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Tang, H. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Grandvaux, N. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Ruscetti, M. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Kossenkov, A. in: JCI | PubMed | Google Scholar |

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Preston-Alp, S. in: JCI | PubMed | Google Scholar

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Tempera, I. in: JCI | PubMed | Google Scholar

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Auslander, N. in: JCI | PubMed | Google Scholar

1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, United States of America

2Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, India

3Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy

4Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, United States of America

5Biochimie et de médecine moléculaire, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Canada

6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States of America

7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, United States of America

Find articles by Altieri, D. in: JCI | PubMed | Google Scholar |

Published August 30, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI180983.
Copyright © 2024, Perego et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 30, 2024 - Version history
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Abstract

The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and a link to tumor suppression undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson’s Disease was epigenetically silenced in cancer and its re-expression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NFκB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8 T cell markers, lowered the expression of immune inhibitory receptors, TIM3 and LAG3, and stimulated high content of the self-renewal/stem cell factor, TCF1. Parkin-induced CD8 T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth, in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.

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  • Version 1 (August 30, 2024): In-Press Preview
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