Abstract / Description of output
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
Original language | English |
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Pages (from-to) | 630-641 |
Journal | Cell Reports |
Volume | 24 |
Issue number | 3 |
Early online date | 17 Jul 2018 |
DOIs | |
Publication status | E-pub ahead of print - 17 Jul 2018 |
Keywords / Materials (for Non-textual outputs)
- ALIX
- EGFR
- ILV
- PD-L1
- breast
- exosome
- Immunosuppression
- tumor