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Plasma Membrane Dynamics Regulating the PD-1/PD-L1 Pathway

Bricogne, CC; (2015) Plasma Membrane Dynamics Regulating the PD-1/PD-L1 Pathway. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The PD-1/PD-L1 pathway in T lymphocytes is emerging as one of the most promising targets for cancer immunotherapy but few details are yet known about how its inhibitory influence is achieved. This work set out to investigate the role of plasma membrane dynamics, on both T cells and tumour cells, in modulating the pathway. In eukaryotic cells, calcium influx leads to rapid changes in the plasma membrane. Exocytosis, phospholipid scrambling, membrane shedding and massive endocytosis can all occur. The calcium sensors for these processes, their inter-dependence and their effects on transmembrane protein expression remain largely unknown. Here we show that the ion channel TMEM16F is the calcium sensor for large exocytosis and that phospholipid scrambling and microvesicle shedding are coupled to exocytosis. The absence of TMEM16F not only abrogates exocytosis but also results in massive endocytosis in response to calcium. Intracellular polyamines regulate these phenotypes, switching cell responses from massive exo- to endocytosis by blocking the TMEM16F conductance. This massive endocytosis also occurs during apoptosis via a calcium-independent mechanism. In lymphocytes, PD-1 participates selectively in both shedding and massive endocytosis, targeting that depends on the PD-1 transmembrane region, independent of actin and classical protein adaptors. We also found that PD-L1 on tumour cells can be transferred to lymphocytes, and be maintained in stable complex with PD-1 on in vitro and in vivo. This may modulate the PD-L1/PD-1 pathway in tumours. Together, these results provide new insights into the plasma membrane reorganization that occurs following calcium transients, establishes a mechanism of PD-1 regulation dependent solely on protein-membrane interaction, and also introduces a new modality by which PD-L1:PD-1 interactions can be sustained beyond cell-cell contact in tumours.

Type: Thesis (Doctoral)
Title: Plasma Membrane Dynamics Regulating the PD-1/PD-L1 Pathway
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: PD-1, Immunology, Cancer Immunology, Cancer Immunotherapy, Calcium, TMEM16F, Massive Endocytosis, Exocytosis, Membrane Shedding
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: http://discovery.ucl.ac.uk/id/eprint/1473199
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