Details

Autor(en) / Beteiligte

• 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

Titel

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation

Ist Teil von

• Cell reports (Cambridge), 2018-07, Vol.24 (3), p.630-641

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •ALIX regulates EGFR activity and PD-L1 surface presentation in breast cancer cells•PD-L1 is packaged into the exosomes of breast cancer cells•ALIX depletion results in reduced exosomal and increased surface PD-L1 expression•Increased surface PD-L1 is associated with an enhanced immunosuppressive phenotype 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.