Drp1 Controls Effective T Cell Immune-Surveillance by Regulating T Cell Migration, Proliferation, and cMyc-Dependent Metabolic Reprogramming

Simula, Luca; Pacella, Ilenia; Colamatteo, Alessandra; Procaccini, Claudio; Cancila, Valeria; Bordi, Matteo; Tregnago, Claudia; Corrado, Mauro; Pigazzi, Martina; Barnaba, Vincenzo; Tripodo, Claudio; Matarese, Giuseppe; Piconese, Silvia; Campello, Silvia

doi:10.1016/j.celrep.2018.11.018

Cited by 97 publications

(146 citation statements)

References 52 publications

(90 reference statements)

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“…Downregulation of MAPK-dependent protein Bim may correlate with defective AICD response in T-ALL cells JNK1, ERK1/2 and Drp1 are activated both during the first proliferation-driving and the second AICD-inducing TCRdependent stimulation of T cells [8,29,30]. By contrast, Bim has mainly a pro-apoptotic role [31].…”

Section: Drp1 and Bim Mediate Cytochrome-c Release Downstream Of Mapkmentioning

confidence: 99%

“…Western blot were performed as previously described [8]. To isolate Opa1 oligomers, cells have been pre-treated with 1 mM BMH (bismaleimidohexane, Thermo Fisher…”

Section: Western Blotmentioning

confidence: 99%

“…Besides Fas/FasL pathway, additional pathways have been proposed to regulate AICD in T cells [6], such as Mitogen-Activated Protein Kinase (MAPK) pathway [7]. Although it regulates several apoptosis-related proteins, such as Drp1, Bim and Nur77 [8][9][10][11], how and when MAPK pathway is playing a role during AICD is still not known.…”

Section: Introductionmentioning

confidence: 99%

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JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction

et al. 2020

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The Activation-Induced Cell Death (AICD) is a stimulation-dependent form of apoptosis used by the organism to shutdown T-cell response once the source of inflammation has been eliminated, while allowing the generation of immune memory. AICD is thought to progress through the activation of the extrinsic Fas/FasL pathway of cell death, leading to cytochrome-C release through caspase-8 and Bid activation. We recently described that, early upon AICD induction, mitochondria undergo structural alterations, which are required to promote cytochrome-C release and execute cell death. Here, we found that such alterations do not depend on the Fas/FasL pathway, which is instead only lately activated to amplify the cell death cascade. Instead, such alterations are primarily dependent on the MAPK proteins JNK1 and ERK1/2, which, in turn, regulate the activity of the pro-fission protein Drp1 and the pro-apoptotic factor Bim. The latter regulates cristae disassembly and cooperate with Drp1 to mediate the Mitochondrial Outer Membrane Permeabilization (MOMP), leading to cytochrome-C release. Interestingly, we found that Bim is also downregulated in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells, this alteration favouring their escape from AICD-mediated control.

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Section: Drp1 and Bim Mediate Cytochrome-c Release Downstream Of Mapkmentioning

confidence: 99%

“…Western blot were performed as previously described [8]. To isolate Opa1 oligomers, cells have been pre-treated with 1 mM BMH (bismaleimidohexane, Thermo Fisher…”

Section: Western Blotmentioning

confidence: 99%

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JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction

et al. 2020

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“…Of note, most of those Drp1-dependent processes are the same that appear to be downregulated by PD-1 inhibitory signaling, especially when considering tumor-infiltrating T cells. Indeed, PD-1 signaling reduces T cell proliferation and motility (both of them requiring Drp1) (4,15,21), and it also promotes a shift from a glycolysis-based metabolism (supported by Drp1) toward an OXPHOS-based metabolism (requiring mitochondrial fusion) (22). Given this striking inverse correlation, we asked whether PD-1 signaling may modulate Drp1 activity, and to what extent this modulation may down-regulate several processes in T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Also, Drp1-dependent mitochondria relocation at the immunological synapse controls the influx of calcium upon T cell activation (17), sustaining the cMyc-dependent upregulation of glycolytic enzymes (15,18), thus allowing the metabolic reprogramming required to cope with the increased bioenergetic demand of an activated T cell (19,20). All these processes contribute to an optimal anti-tumor T cell response, which is indeed defective in T cells lacking Drp1 (15).…”

Section: Introductionmentioning

confidence: 99%

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

Simula

Cancila

Antonucci

et al. 2020

Preprint

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PD-1 signalling downregulates the T cell response, promoting an exhausted state in tumor-infiltrating 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 tumor-infiltrating 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.

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

et al. 2021

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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‐1 pos CD8 + T cells infiltrating an MC38 (murine adenocarcinoma)‐derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD‐1 neg counterparts. Also, PD‐1 pos 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‐1 pos 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.

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Drp1 Controls Effective T Cell Immune-Surveillance by Regulating T Cell Migration, Proliferation, and cMyc-Dependent Metabolic Reprogramming

Cited by 97 publications

References 52 publications

JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction

JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction

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

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

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