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

James Monypenny; Hanna Milewicz; Fabian Flores-Borja; Gregory Weitsman; Anthony Cheung; Ruhe Chowdhury; Thomas Burgoyne; Appitha Arulappu; Katherine Lawler; Paul R. Barber; Jose M. Vicencio; Melanie Keppler; Wahyu Wulaningsih; Sean M. Davidson; Franca Fraternali; Natalie Woodman; Mark Turmaine; Cheryl Gillett; Dafne Franz; Sergio A. Quezada; Clare E. Futter; Alex Von Kriegsheim; Walter Kolch; Borivoj Vojnovic; Jeremy G. Carlton; Tony Ng

doi:10.1016/j.celrep.2018.06.066

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

James Monypenny, Hanna Milewicz, Fabian Flores-Borja, Gregory Weitsman, Anthony Cheung, Ruhe Chowdhury, Thomas Burgoyne, Appitha Arulappu, Katherine Lawler, Paul R. Barber, Jose M. Vicencio, Melanie Keppler, Wahyu Wulaningsih, Sean M. Davidson, Franca Fraternali, Natalie Woodman, Mark Turmaine, Cheryl Gillett, Dafne Franz, Sergio A. QuezadaClare E. Futter, Alex Von Kriegsheim, Walter Kolch, Borivoj Vojnovic, Jeremy G. Carlton, Tony Ng

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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.

Original language	English
Pages (from-to)	630-641
Number of pages	12
Journal	Cell Reports
Volume	24
Issue number	3
Early online date	17 Jul 2018
DOIs	https://doi.org/10.1016/j.celrep.2018.06.066
Publication status	Published - 17 Jul 2018

Keywords

ALIX
PD-L1
EGFR
exosome
ILV
immunosuppression
tumor
breast
lymphocyte

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Monypenny, J., Milewicz, H., Flores-Borja, F., Weitsman, G., Cheung, A., Chowdhury, R., Burgoyne, T., Arulappu, A., Lawler, K., Barber, P. R., Vicencio, J. M., Keppler, M., Wulaningsih, W., Davidson, S. M., Fraternali, F., Woodman, N., Turmaine, M., Gillett, C., Franz, D., ... Ng, T. (2018). ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation. Cell Reports, 24(3), 630-641. https://doi.org/10.1016/j.celrep.2018.06.066

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title = "ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation",

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, PD-L1, EGFR, exosome, ILV, immunosuppression, tumor, breast, lymphocyte",

author = "James Monypenny and Hanna Milewicz and Fabian Flores-Borja and Gregory Weitsman and Anthony Cheung and Ruhe Chowdhury and Thomas Burgoyne and Appitha Arulappu and Katherine Lawler and Barber, {Paul R.} and Vicencio, {Jose M.} and Melanie Keppler and Wahyu Wulaningsih and Davidson, {Sean M.} and Franca Fraternali and Natalie Woodman and Mark Turmaine and Cheryl Gillett and Dafne Franz and Quezada, {Sergio A.} and Futter, {Clare E.} and {Von Kriegsheim}, Alex and Walter Kolch and Borivoj Vojnovic and Carlton, {Jeremy G.} and Tony Ng",

year = "2018",

month = jul,

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doi = "10.1016/j.celrep.2018.06.066",

language = "English",

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Monypenny, J , Milewicz, H , Flores-Borja, F , Weitsman, G , Cheung, A , Chowdhury, R, Burgoyne, T, Arulappu, A , Lawler, K, Barber, PR, Vicencio, JM, Keppler, M , Wulaningsih, W, Davidson, SM, Fraternali, F, Woodman, N, Turmaine, M, Gillett, C, Franz, D, Quezada, SA, Futter, CE, Von Kriegsheim, A, Kolch, W, Vojnovic, B , Carlton, JG & Ng, T 2018, 'ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation', Cell Reports, vol. 24, no. 3, pp. 630-641. https://doi.org/10.1016/j.celrep.2018.06.066

TY - JOUR

T1 - ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation

AU - Monypenny, James

AU - Milewicz, Hanna

AU - Flores-Borja, Fabian

AU - Weitsman, Gregory

AU - Cheung, Anthony

AU - Chowdhury, Ruhe

AU - Burgoyne, Thomas

AU - Arulappu, Appitha

AU - Lawler, Katherine

AU - Barber, Paul R.

AU - Vicencio, Jose M.

AU - Keppler, Melanie

AU - Wulaningsih, Wahyu

AU - Davidson, Sean M.

AU - Fraternali, Franca

AU - Woodman, Natalie

AU - Turmaine, Mark

AU - Gillett, Cheryl

AU - Franz, Dafne

AU - Quezada, Sergio A.

AU - Futter, Clare E.

AU - Von Kriegsheim, Alex

AU - Kolch, Walter

AU - Vojnovic, Borivoj

AU - Carlton, Jeremy G.

AU - Ng, Tony

PY - 2018/7/17

Y1 - 2018/7/17

N2 - 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.

AB - 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.

KW - ALIX

KW - PD-L1

KW - EGFR

KW - exosome

KW - ILV

KW - immunosuppression

KW - tumor

KW - breast

KW - lymphocyte

UR - http://www.scopus.com/inward/record.url?scp=85049748724&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.06.066

DO - 10.1016/j.celrep.2018.06.066

M3 - Article

SN - 2211-1247

VL - 24

SP - 630

EP - 641

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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