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Cell Rep. 2018 Jul 17;24(3):630-641. doi: 10.1016/j.celrep.2018.06.066.

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation.

Author information

1
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK.
2
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; KCL Breast Cancer Now Research Unit, Department of Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK.
3
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, Great Maze Pond, London, UK.
4
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
5
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; Institute for Mathematical and Molecular Biomedicine, King's College London, Guy's Medical School Campus, London SE1 1UL, UK.
6
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK.
7
UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK.
8
Cancer Epidemiology Group, Division of Cancer Studies, King's College London, London, UK.
9
Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK.
10
Bioinformatics and Computational Biology, Randall Division, King's College London, Guy's Medical School Campus, London SE1 1UL, UK.
11
KHP Cancer Biobank, King's College London, Innovation Hub, Guy's Cancer Centre, London SE1 9RT, UK.
12
Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.
13
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
14
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
15
Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
16
Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, Great Maze Pond, London, UK; Organelle Dynamics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: jeremy.carlton@kcl.ac.uk.
17
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; KCL Breast Cancer Now Research Unit, Department of Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK; UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK. Electronic address: tony.ng@kcl.ac.uk.

Abstract

The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT)-associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells. An inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immunocompetent mouse model of breast cancer revealed that ALIX-deficient tumors are larger and show an increased immunosuppressive environment. Our data suggest that ALIX modulates immunosuppression through regulation of PD-L1 and EGFR and may, therefore, present a diagnostic and therapeutic target for BLBC.

KEYWORDS:

ALIX; EGFR; ILV; PD-L1; breast; exosome; immunosuppression; lymphocyte; tumor

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