| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 24, Iss 3, Pp 630-641 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2018.06.066 |
| Popis: |
Summary: 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. : Monypenny et al. show that the ESCRT-related protein ALIX regulates two clinically important proteins in breast cancer; namely, EGFR, a receptor linked to cell survival, and PD-L1, an immune checkpoint protein. ALIX is, therefore, associated with pathways that drive both cell-autonomous and non-cell-autonomous mechanisms of tumor survival. Keywords: ALIX, PD-L1, EGFR, exosome, ILV, immunosuppression, tumor, breast, lymphocyte |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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