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-induced T cell exhaustion is controlled by a Drp1-dependent mechanism / 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.. - In: MOLECULAR ONCOLOGY. - ISSN 1574-7891. - 16:1(2022), pp. 188-205. [10.1002/1878-0261.13103]

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

Scarpelli G.;Colamatteo A.;De Angelis B.;Quintarelli C.;Matarese G.;
2022

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.
2022
PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism / 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.. - In: MOLECULAR ONCOLOGY. - ISSN 1574-7891. - 16:1(2022), pp. 188-205. [10.1002/1878-0261.13103]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/879963
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