ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation

Journal Article: Cell ReportsYear Published: (2018) Volume Number: 24, Article Number: 630-641

Authors

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

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.