PD‐1‐induced T cell exhaustion is controlled by a Drp1‐dependent mechanism
| العنوان: | PD‐1‐induced T cell exhaustion is controlled by a Drp1‐dependent mechanism |
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| المؤلفون: | Giuseppe Matarese, Biagio De Angelis, Valeria Cancila, Giorgia Scarpelli, Claudio Procaccini, Silvia Campello, Luca Simula, Claudio Tripodo, Alessandra Colamatteo, Simona Manni, Ylenia Antonucci, Concetta Quintarelli |
| المساهمون: | Simula L., Antonucci Y., Scarpelli G., Cancila V., Colamatteo A., Manni S., De Angelis B., Quintarelli C., Procaccini C., Matarese G., Tripodo C., Campello S., Simula, L., Antonucci, Y., Scarpelli, G., Cancila, V., Colamatteo, A., Manni, S., De Angelis, B., Quintarelli, C., Procaccini, C., Matarese, G., Tripodo, C., Campello, S. |
| المصدر: | Molecular Oncology, Vol 16, Iss 1, Pp 188-205 (2022) Molecular Oncology |
| بيانات النشر: | Wiley, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Dynamins, Cancer Research, endocrine system, Settore BIO/06, T cell, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Drp1, CD8-Positive T-Lymphocytes, Settore MED/08 - Anatomia Patologica, Mitochondrial Dynamics, tumor‐infiltrating lymphocytes, Mice, Immune system, Downregulation and upregulation, Drp1, mitochondria, PD-1, T cell, tumor-infiltrating lymphocytes, PD-1, Genetics, medicine, Animals, Humans, Settore MED/05 - Patologia Clinica, Research Articles, PI3K/AKT/mTOR pathway, RC254-282, Tumor-infiltrating lymphocytes, Chemistry, PD‐1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Immunotherapy, Cell biology, mitochondria, medicine.anatomical_structure, Oncology, tumor-infiltrating lymphocytes, Molecular Medicine, Mitochondrial fission, CD8, Research Article |
| الوصف: | 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. PD‐1 signaling prevents TCR‐dependent Drp1 activation and subsequent mitochondrial fragmentation in T cells. In turn, this reduces both proliferation and migration of activated T cells. Cancer cells exploit this mechanism to downregulate T‐cell functionality within the tumor microenvironment, favoring tumor progression. These findings shed light on a new possible therapeutical approach for the treatment of solid cancers. (image made in BioRender). |
| اللغة: | English |
| تدمد: | 1574-7891 1878-0261 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::07ca9f40c8f382ed460086062013790fTest https://doaj.org/article/c6c81d19bafd46319ecd1f043d0fc599Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....07ca9f40c8f382ed460086062013790f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15747891 18780261 |
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