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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Parkin activates innate immunity and promotes antitumor immune responses
Michela Perego1, Minjeong Yeon1, Ekta Agarwal1
1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
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.
Insights
Parkin, a tumor suppressor, reactivates innate immunity and interferon signaling in cancer cells. This Parkin-mediated pathway inhibits tumor growth by enhancing CD8+ T cell responses and suppressing immune evasion.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Innate immunity and interferon (IFN) signaling are implicated in cancer, but their regulators and tumor suppression roles are unclear.
- Parkin, an E3 ubiquitin ligase linked to Parkinson's Disease, is epigenetically silenced in cancer.
Purpose of the Study:
- To investigate Parkin's role in cancer immunity and tumor suppression.
- To determine if Parkin reexpression can restore anti-tumor immunity.
Main Methods:
- Epigenetic analysis of Parkin in cancer.
- Reexpression of Parkin using demethylating therapy.
- Assessment of IFN response, High Mobility Group Box 1 (HMGB1) release, and NF-κB signaling.
- Analysis of CD8+ T cell markers, immune checkpoints (TIM3, LAG3), and TCF1 in Parkin-expressing cells.
- In vivo studies using transgenic and syngeneic tumor models.
Main Results:
- Parkin reexpression via demethylating therapy induced a potent IFN response in tumor cells.
- Parkin's E3 ubiquitin ligase activity mediated HMGB1 release and suppressed NF-κB.
- Parkin-induced IFN secretome enhanced CD8+ T cell effector functions and TCF1, while reducing immune suppression.
- Parkin-expressing CD8+ T cells accumulated in tumors and inhibited tumor growth in vivo.
Conclusions:
- Parkin acts as an epigenetically regulated activator of innate immunity.
- Parkin functions as a dual-mode tumor suppressor by inhibiting intrinsic tumor traits and enhancing anti-tumor T cell immunity.
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