PT  - JOURNAL ARTICLE
AU  - Luca Simula
AU  - Valeria Cancila
AU  - Ylenia Antonucci
AU  - Alessandra Colamatteo
AU  - Claudio Procaccini
AU  - Giuseppe Matarese
AU  - Claudio Tripodo
AU  - Silvia Campello
TI  - PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism
AID  - 10.1101/2020.07.14.200592
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.14.200592
4099  - http://biorxiv.org/content/early/2020/07/14/2020.07.14.200592.short
4100  - http://biorxiv.org/content/early/2020/07/14/2020.07.14.200592.full
AB  - PD-1 signalling downregulates the T cell response, promoting an exhausted state in tumorinfiltrating T cells, through mostly unveiled molecular mechanisms. Drp1-dependent mitochondrial fission plays a crucial role to sustain T cell motility, proliferation, survival and glycolytic engagement and, interestingly, such processes are exactly those inhibited by PD-1 in tumorinfiltrating T cells. Here we show that pD1positive CD8+ T cells infiltrating MC38-derived murine tumor mass show downregulated Drp1 activity and more fused mitochondria compared to PD1negative counterparts. Also, PD1positive lymphocytic elements infiltrating human colon cancer almost never express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondria fragmentation following T cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 pathway and, to a lesser extent, of mTOR. In addition, downregulation of Drp1 activity in tumor-infiltrating PD1positive 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 anti-cancer immune response in future immunotherapy approaches.Competing Interest StatementThe authors have declared no competing interest.