ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentationMore about Open Access at the Crick
Authors listJames 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 Carlton Tony Ng
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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.