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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 5

PRKN deletion accelerates prostate tumorigenesis.

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PRKN deletion accelerates prostate tumorigenesis.
(A) Male TRAMP or TRAM...
(A) Male TRAMP or TRAMP-PRKN–KO mice were analyzed for prostate tumor formation by IHC at 26 wks of age. (B) Representative macroscopic images of prostate tumors formed in TRAMP (29 wks) or TRAMP-PRKN KO (25 wks) mice. (C) Tumors harvested from TRAMP or TRAMP-PRKN–KO mice at 30 wks were analyzed for a disease severity (tumor size, hemorrhage, and seminal vesicle invasion; cutoff = 3). For panels A and C, the number of animals is indicated. (D) Prostate tissues from the indicated mouse groups at 26 wks were analyzed by H&E staining (left) or intratumoral accumulation of CD8+ T cells, by IHC (right). The percentage of cells is indicated. Representative images. Scale bar: 100 μm. (E) Plasma samples from C57BL/6 (WT), TRAMP, or TRAMP-PRKN–KO mice were analyzed for IFN-α (top) or IL6 (bottom) levels, by ELISA. Each point corresponds to an individual determination. (F) Prostate tissues from TRAMP or TRAMP-PRKN–KO mice were harvested at 26 wks and analyzed for the indicated immune cell subsets by flow cytometry. DC, dendritic cells; Mono, monocytes; Macro, macrophages. (G) The conditions are the same as in F and residual intratumoral CD8+ T cells were analyzed for expression of the indicated markers by flow cytometry. For all panels, mean ± SD. (H) The conditions are the same as in G and the percentage of TCF1+ CD8+ T cells was quantified in TRAMP or TRAMP-PRKN–KO mice (26 wks) by flow cytometry. Representative density plots are shown. (I) The conditions are the same as in G and geometrical mean fluorescence intensity for PD-1 (top) or LAG3 (bottom) expression in CD8+ T cells from TRAMP or TRAMP-PRKN–KO mice is indicated. Mean ± SD. Each point corresponds to an individual determination. Numbers represent P values by 2-tailed unpaired t test.

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

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