ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
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Elsevier
2018
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| _version_ | 1826290526934007808 |
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| author | Monypenny, J Milewicz, H Flores-Borja, F Weitsman, G Cheung, A Chowdhury, R Burgoyne, T Arulappu, A Lawler, K Barber, P Vicencio, J Keppler, M Wulaningsih, W Davidson, S Fraternali, F Woodman, N Turmaine, M Gillett, C Franz, D Quezada, S Futter, C Von Kriegsheim, A Kolch, W Vojnovic, B Carlton, J Ng, T |
| author_facet | Monypenny, J Milewicz, H Flores-Borja, F Weitsman, G Cheung, A Chowdhury, R Burgoyne, T Arulappu, A Lawler, K Barber, P Vicencio, J Keppler, M Wulaningsih, W Davidson, S Fraternali, F Woodman, N Turmaine, M Gillett, C Franz, D Quezada, S Futter, C Von Kriegsheim, A Kolch, W Vojnovic, B Carlton, J Ng, T |
| author_sort | Monypenny, J |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:45:33Z |
| format | Journal article |
| id | oxford-uuid:abf24b3b-15d7-4326-b8ad-9450485b2c88 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T02:45:33Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:abf24b3b-15d7-4326-b8ad-9450485b2c882022-03-27T03:25:24ZALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:abf24b3b-15d7-4326-b8ad-9450485b2c88Symplectic Elements at OxfordElsevier2018Monypenny, JMilewicz, HFlores-Borja, FWeitsman, GCheung, AChowdhury, RBurgoyne, TArulappu, ALawler, KBarber, PVicencio, JKeppler, MWulaningsih, WDavidson, SFraternali, FWoodman, NTurmaine, MGillett, CFranz, DQuezada, SFutter, CVon Kriegsheim, AKolch, WVojnovic, BCarlton, JNg, TThe 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. |
| spellingShingle | Monypenny, J Milewicz, H Flores-Borja, F Weitsman, G Cheung, A Chowdhury, R Burgoyne, T Arulappu, A Lawler, K Barber, P Vicencio, J Keppler, M Wulaningsih, W Davidson, S Fraternali, F Woodman, N Turmaine, M Gillett, C Franz, D Quezada, S Futter, C Von Kriegsheim, A Kolch, W Vojnovic, B Carlton, J Ng, T ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation |
| title | ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation |
| title_full | ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation |
| title_fullStr | ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation |
| title_full_unstemmed | ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation |
| title_short | ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation |
| title_sort | alix regulates tumor mediated immunosuppression by controlling egfr activity and pd l1 presentation |
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