PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism.

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.

• Authors: Luca Simula, Ylenia Antonucci, Giorgia Scarpelli, Valeria Cancila, Alessandra Colamatteo, Simona Manni, Biagio De Angelis, Concetta Quintarelli, Claudio Procaccini, Giuseppe Matarese, Claudio Tripodo, Silvia Campello
• Journal: Molecular oncology (Mol Oncol) Vol. 16 Issue 1 Pg. 188-205 (01 2022) ISSN: 1878-0261 [Electronic] United States
• PMID: 34535949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Dnm1l protein, mouse
• Dynamins

Topics

• Animals
• CD8-Positive T-Lymphocytes (metabolism)
• Dynamins (immunology, metabolism)
• Humans
• Mice
• Mitochondria (metabolism)
• Mitochondrial Dynamics
• Programmed Cell Death 1 Receptor (immunology, metabolism)