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Published on: July 20, 2019
Isoliensinine inhibits mitophagy and sensitizes T cell malignancies for STING-mediated NK clearance
Xiao Ge1,2, Guang-Ming Yang1, Xiao-Long Zhang1
1School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Abstract:
Mitochondrial DNA (mtDNA) damage and accumulation activate the cGAS-STING DNA-sensing pathway, which promotes immune clearance of tumor cells. Maintenance of the cytosolic level of mtDNA is key to sustain immune activation. T cell malignancies (T-CMs) are a general name of diseases with abnormal clonal proliferation of T lymphocytes at various stages. Immunotherapy of T-CMs is challenged by the lack of specific antigens to discriminate T-CMs from normal T cells. As intrinsic STING activation can promote the clearance of T-CMs by immune cells, we herein explored whether isoliensinine (IsoL), a natural compound from Nelumbinis Plumula could enhance NK clearance by mtDNA-mediated immune responses in tumor cells. To investigate whether IsoL modulated immune recognition and clearance of T-CMs, we pre-treated three T-CM cell lines (Jurkat, Molt4 and Hut102) with IsoL then co-cultured with NK-92MI cells. We showed that IsoL pre-treatment promoted cytosolic mtDNA accumulation by inducing ROS-dependent mitochondrial damage and inhibiting mitophagy via peroxiredoxin 1 (PRDX1), an antioxidant enzyme. Loss of PRDX1 in T-CMs also induced ROS-dependent mitochondrial DNA damage, and blocked mitophagy by preventing accumulation of mature PINK1, which was required to initiate mitophagy via recruiting Parkin to the damaged mitochondria. Remarkably, IsoL could induce expression of activating ligands in vitro, enhance NK cell infiltrations, and increase apoptosis of T-CMs. Moreover, we demonstrated that IsoL could sensitize T-CMs for NK clearance in vitro and in vivo. These results suggest that IsoL could be a potential therapeutic agent to enhance immune therapy of T-CMs.
Insights
Isoliensinine (IsoL) enhances natural killer (NK) cell clearance of T cell malignancies (T-CMs) by promoting mitochondrial DNA (mtDNA) release and immune activation. This natural compound shows potential for improving T-CM immunotherapy.
Area of Science:
- Immunology
- Oncology
- Mitochondrial Biology
Background:
- Mitochondrial DNA (mtDNA) damage and release activate the cGAS-STING pathway, crucial for tumor cell immune clearance.
- T cell malignancies (T-CMs) lack specific antigens for targeted immunotherapy, necessitating alternative strategies.
- Intrinsic STING activation offers a potential mechanism for T-CM clearance by immune cells.
Purpose of the Study:
- To investigate if isoliensinine (IsoL) enhances NK cell-mediated clearance of T-CMs via mtDNA-driven immune responses.
- To explore IsoL's effects on immune recognition and clearance of T-CMs.
Main Methods:
- T-CM cell lines (Jurkat, Molt4, Hut102) were pre-treated with IsoL and co-cultured with NK-92MI cells.
- Assessed IsoL's impact on cytosolic mtDNA levels, reactive oxygen species (ROS), mitophagy, and PRDX1/PINK1/Parkin pathways.
- Evaluated IsoL's effects on activating ligand expression, NK cell infiltration, T-CM apoptosis, and therapeutic efficacy in vitro and in vivo.
Main Results:
- IsoL pre-treatment increased cytosolic mtDNA accumulation by inducing ROS-dependent mitochondrial damage and inhibiting mitophagy via peroxiredoxin 1 (PRDX1).
- Loss of PRDX1 mimicked IsoL's effects, inducing mitochondrial damage and blocking mitophagy by preventing PINK1 accumulation.
- IsoL enhanced T-CM apoptosis, upregulated activating ligands, increased NK cell infiltration, and sensitized T-CMs to NK clearance in vitro and in vivo.
Conclusions:
- Isoliensinine promotes T-CM immune clearance by inducing mtDNA release and enhancing NK cell activity.
- IsoL's mechanism involves ROS-dependent mitochondrial damage, inhibited mitophagy, and modulation of key regulatory proteins.
- IsoL represents a promising therapeutic agent for augmenting immunotherapy in T cell malignancies.
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