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Published on: October 15, 2013
PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism
Luca Simula1, Ylenia Antonucci1, Giorgia Scarpelli1
1Department of Biology, University of Rome Tor Vergata, Rome, Italy.
Abstract:
Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1neg counterparts. Also, PD-1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondrial fragmentation following T-cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1pos CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.
Insights
Programmed cell death-1 (PD-1) signaling inhibits T-cell anti-cancer activity by reducing Dynamin-related protein-1 (Drp1) activity, leading to elongated mitochondria and impaired T-cell function. Modulating Drp1 offers a potential immunotherapy target.
Area of Science:
- Immunology
- Cancer Biology
- Mitochondrial Biology
Background:
- Programmed cell death-1 (PD-1) signaling suppresses T-cell responses in tumors via unclear mechanisms.
- Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission is vital for T-cell function, including motility and proliferation.
- PD-1 signaling inhibits these essential T-cell processes.
Purpose of the Study:
- To investigate the role of Drp1 activity in PD-1-mediated T-cell exhaustion.
- To elucidate the molecular mechanisms linking PD-1 signaling to Drp1 regulation.
- To assess the therapeutic potential of targeting Drp1 in cancer immunotherapy.
Main Methods:
- Analysis of Drp1 activity and mitochondrial morphology in PD-1 positive versus negative CD8+ T cells from murine (MC38) and human (colon cancer) tumors.
- Investigating the impact of PD-1 signaling on Drp1 phosphorylation at Ser616.
- Examining the involvement of ERK1/2 and mTOR pathways in PD-1-mediated Drp1 regulation.
Main Results:
- PD-1+ T cells in tumors exhibit reduced Drp1 activity and elongated mitochondria compared to PD-1- counterparts.
- Active Drp1 is rarely found in PD-1+ lymphocytes infiltrating human colon cancer.
- PD-1 signaling directly downregulates Drp1 phosphorylation at Ser616 via ERK1/2 and mTOR pathways, inhibiting mitochondrial fragmentation.
- Reduced Drp1 activity contributes to impaired T-cell motility and proliferation under PD-1 signaling.
Conclusions:
- PD-1 signaling suppresses anti-tumor T-cell responses by inhibiting Drp1-dependent mitochondrial fission.
- This mechanism impairs T-cell motility and proliferation, contributing to immune exhaustion.
- Targeting Drp1 activity in tumor-infiltrating T cells represents a promising strategy for enhancing cancer immunotherapy.
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