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.
Highlights
Programmed cell death-1 (PD-1) is a T-cell surface receptor that downregulates T-cell activation and the immune response [1]
PD-1 signaling is activated by PD-1 interaction with its ligands PD-1 ligand 1 (PD-L1) and PD-1 ligand 2 (PD-L2), expressed on adjacent cells [2], and it dampens signals originating from T-cell receptor (TCR) and CD28, such as the activation of mammalian target of rapamycin and mitogen-activated protein kinase (MAPK) pathways [3,4]
dynamin-related protein-1 (Drp1)-dependent mitochondrial relocation at the immunological synapse controls the influx of calcium upon T-cell activation [14], sustaining the cMyc-dependent upregulation of glycolytic enzymes [13,15], allowing the metabolic reprogramming required to cope with the increased bioenergetic demand of an activated T cell [16,17]
Summary
Programmed cell death-1 (PD-1) is a T-cell surface receptor that downregulates T-cell activation and the immune response [1]. Drp1-dependent mitochondrial relocation at the immunological synapse controls the influx of calcium upon T-cell activation [14], sustaining the cMyc-dependent upregulation of glycolytic enzymes [13,15], allowing the metabolic reprogramming required to cope with the increased bioenergetic demand of an activated T cell [16,17]. All these processes contribute to an optimal antitumor T-cell response, which is defective in T cells lacking Drp1 [13]
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