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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...

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Detalles Bibliográficos
Autores principales: Monypenny, James, Milewicz, Hanna, Flores-Borja, Fabian, Weitsman, Gregory, Cheung, Anthony, Chowdhury, Ruhe, Burgoyne, Thomas, Arulappu, Appitha, Lawler, Katherine, Barber, Paul R., Vicencio, Jose M., Keppler, Melanie, Wulaningsih, Wahyu, Davidson, Sean M., Fraternali, Franca, Woodman, Natalie, Turmaine, Mark, Gillett, Cheryl, Franz, Dafne, Quezada, Sergio A., Futter, Clare E., Von Kriegsheim, Alex, Kolch, Walter, Vojnovic, Borivoj, Carlton, Jeremy G., Ng, Tony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077252/
https://www.ncbi.nlm.nih.gov/pubmed/30021161
http://dx.doi.org/10.1016/j.celrep.2018.06.066
Descripción
Sumario: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.