期刊
CELL REPORTS
卷 24, 期 3, 页码 630-641出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.06.066
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资金
- Cancer Research UK [C1519/A6906, C5255/A15935]
- King's College London-UCL Comprehensive Cancer Imaging Centre (CRUK)
- King's College London-UCL Comprehensive Cancer Imaging Centre (EPSRC) [C1519/A10331, C1519/A16463]
- MRC
- DoH [C1519/A10331]
- EU FP7 grants IMAGINT (EC grant) [259881]
- KCL Breast Cancer Now Unit funding [KCL-Q2-Y5]
- Dimbleby Cancer Care
- MRC [G1001684, MR/P010091/1] Funding Source: UKRI
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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