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

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posted on 07.09.2020 by 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
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.

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