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Parkin activates innate immunity and promotes antitumor immune responses
Michela Perego, … , Noam Auslander, Dario C. Altieri
Michela Perego, … , Noam Auslander, Dario C. Altieri
Published August 30, 2024
Citation Information: J Clin Invest. 2024;134(22):e180983. https://doi.org/10.1172/JCI180983.
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Research Article Immunology Oncology Article has an altmetric score of 99

Parkin activates innate immunity and promotes antitumor immune responses

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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 links to tumor suppression remain undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson’s Disease, was epigenetically silenced in cancer and its reexpression 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 NF-κB 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. PRKN-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.

Authors

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

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Figure 4

Paracrine CD8 T cell activation by PRKN IFN signaling.

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Paracrine CD8 T cell activation by PRKN IFN signaling.
(A) Recipient PC3...
(A) Recipient PC3 cells were incubated with CM harvested from PC3 cells expressing vector, PRKN, or PRKN C431S mutant and analyzed for IFN gene expression by RT-qPCR. Mean ± SD (n = 4). Numbers represent P value by 2-way ANOVA. (B) Diagram of flow cytometry gating to characterize CD8+ (left) or CD4+ (right) T cell subsets from CD3+/CD19– splenocytes of C57BL/6 mice. Created with BioRender.com. (C) CD8+ T cells isolated from C57BL/6 splenocytes by negative selection were incubated with CM harvested from PRKN TetON TRAMP-C2 cells in the presence of vehicle or Doxy and analyzed by flow cytometry. Representative plots are shown. The percentage of cells in each quadrant is indicated. (D) The conditions are the same as in C and PRKN CM modulation of CD8+ T cell markers was quantified by flow cytometry in 5 independent experiments. Numbers represent P values by 2-tailed unpaired t test. (E and F) The conditions are the same as in C and double positive PD-1+/TCF1+ CD8+ T cells were analyzed by flow cytometry in representative density plots (E) and results were quantified in 6 independent experiments (F). (G) CD8+ T cells isolated from IFNAR1–/– splenocytes were incubated with CM harvested from PRKN TetON TRAMP-C2 cells as in C and analyzed by flow cytometry in representative density plots. The percentage of cells in each quadrant is indicated. (H) The conditions are the same as in G and modulation of the indicated CD8+ T cell markers was quantified in 6 independent experiments. (I and J) CD8+ T cells isolated from IFNAR1–/– splenocytes were analyzed for double-positive PD-1+/TCF1+ subsets by flow cytometry in representative density plots (I) and results were quantified in 6 independent experiments (J). The percentage of cells in each quadrant is indicated. Symbols indicate an individual determination.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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