Journal
MOLECULAR ONCOLOGY
Volume 16, Issue 1, Pages 188-205Publisher
WILEY
DOI: 10.1002/1878-0261.13103
Keywords
Drp1; mitochondria; PD-1; T cell; tumor-infiltrating lymphocytes
Categories
Funding
- Fondazione AIRC [IG-2017 19826]
- Fondazione AIRC `Fellowship for Italy' [23926]
- Fondazione Italiana Sclerosi Multipla (FISM) [2016/R/18, 2018/S/5]
- Progetti di Rilevante Interesse Nazionale (PRIN) [2017 K55HLC 001]
- Italian Ministry of Health [GR-2016-02363749, GR-2018-12366154, RF-2019-12371111]
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The PD-1 signaling pathway downregulates T-cell response by inhibiting Drp1 activity, leading to reduced motility and proliferation of tumor-infiltrating T cells. This highlights the potential of targeting Drp1 activity as a valuable strategy to enhance anticancer immune response in future immunotherapy approaches.
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-1(pos) CD8(+) T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1(neg) counterparts. Also, PD-1(pos) 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-1(pos) 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.
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