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RESEARCH PRODUCT
PD‐1‐induced T cell exhaustion is controlled by a Drp1‐dependent mechanism
Giuseppe MatareseBiagio De AngelisValeria CancilaGiorgia ScarpelliClaudio ProcacciniSilvia CampelloSilvia CampelloLuca SimulaClaudio TripodoAlessandra ColamatteoSimona ManniYlenia AntonucciConcetta QuintarelliConcetta Quintarellisubject
DynaminsCancer Researchendocrine systemSettore BIO/06T cellmedicine.medical_treatmentProgrammed Cell Death 1 ReceptorDrp1CD8-Positive T-LymphocytesSettore MED/08 - Anatomia PatologicaMitochondrial Dynamicstumor‐infiltrating lymphocytesMiceImmune systemDownregulation and upregulationDrp1 mitochondria PD-1 T cell tumor-infiltrating lymphocytesPD-1GeneticsmedicineAnimalsHumansSettore MED/05 - Patologia ClinicaResearch ArticlesPI3K/AKT/mTOR pathwayRC254-282Tumor-infiltrating lymphocytesChemistryPD‐1T cellNeoplasms. Tumors. Oncology. Including cancer and carcinogensGeneral MedicineImmunotherapyCell biologymitochondriamedicine.anatomical_structureOncologytumor-infiltrating lymphocytesMolecular MedicineMitochondrial fissionCD8Research Articledescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2022-01-01 | Molecular Oncology |