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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 6

PRKN antitumor immunity.

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PRKN antitumor immunity.
(A) C57BL/6 (left) or nude Nu/Nu (right) mice w...
(A) C57BL/6 (left) or nude Nu/Nu (right) mice were engrafted with syngeneic PRKN TetON AT3 cells in the mammary fat pad, and tumor growth was quantified with a caliper. Doxy (500 ng/mL) or vehicle (Veh) was administered in the drinking water (arrow) when tumors reached a volume of approximately 120–150 mm3. Each line is an individual tumor. Two independent experiments (Exp) with Nu/Nu mice are shown. (B) AT3 tumors (as in A) were quantified with a caliper at the end of the experiment. Veh, vehicle; B6, C57BL/6; Nu (Nu/Nu) mice. Mean ± SD. Veh-B6 (n = 10), Doxy-B6 (n = 8), Doxy-Nu (n = 8). (C) AT3 tumors grown in C57BL/6 mice in the presence of vehicle (Veh) or Doxy were analyzed by IHC or H&E staining. Scale bar: 50 μm. (D) CD8+ T cells harvested from PRKN TetON AT3 tumors in vehicle (Veh)- or Doxy-treated C57BL/6 mice were analyzed for the indicated markers by flow cytometry. Arrow indicates an outlier in TIM3 reactivity. (E and F). Intratumoral CD8+ T cells (as in D) were analyzed for double-positive PD1+/TCF1+ (E) or KLRG1+/GrzB+ (F) subsets by flow cytometry. Representative density plots are shown. The percentage of double-positive cells is indicated. For all panels, each point corresponds to an individual determination. (G) CD4+ T cells harvested from PRKN TetON AT3 tumors in vehicle (Veh)- or Doxy-treated C57BL/6 mice were analyzed for the indicated markers by flow cytometry. (H) C57BL/6 mice engrafted with syngeneic flank TRAMP-C2 tumors were administered vehicle (Veh) or decitabine (2.5 mg/kg daily) once tumors reached approximately 150 mm3 (arrow) and tumor growth was quantified with a caliper. (I) TRAMP-C2 tumors harvested from the indicated mouse group were analyzed by IHC. Representative images are shown. Scale bar: 50 μm. 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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